JP4361144B2 - Sustained release formulation - Google Patents
Sustained release formulation Download PDFInfo
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- JP4361144B2 JP4361144B2 JP29977897A JP29977897A JP4361144B2 JP 4361144 B2 JP4361144 B2 JP 4361144B2 JP 29977897 A JP29977897 A JP 29977897A JP 29977897 A JP29977897 A JP 29977897A JP 4361144 B2 JP4361144 B2 JP 4361144B2
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- sustained
- release preparation
- lactic acid
- physiologically active
- acid polymer
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
- A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
- A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/18—Feminine contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
Abstract
Description
【0001】
【発明の属する技術分野】
本発明は、約5カ月以上にわたり生理活性物質を放出する徐放性製剤に関する。
【0002】
【従来の技術】
生体内分解性ポリマーを用いた薬物のマイクロスフェア型徐放性製剤については、例えば特開昭57-118512号(EP-A 52510)、特開昭57-150609号(EP-A 58481)、特開昭60-100516号(EP-A 145240)、特開昭62-201816号(EP-A 190833)、特開平4-321622号(EP-A 442671)、特開平7-97334号(EP-A 601799)などに開示されている。特に、特開昭60-100516号(EP-A 145240)および特開昭62-201816号(EP-A 190833)には、水中乾燥法により、高いトラップ率で、分散性の良い水溶性薬物の徐放性マイクロカプセルを製造する方法が開示されている。また、特開平4-321622号(EP-A 442671)には、乳酸/グリコール酸の組成比が80/20〜100/0で重量平均分子量7,000〜30,000のコポリマーないしホモポリマーを含有し、2カ月以上にわたってポリペプチドをゼロ次放出する長期徐放型マイクロカプセルが開示されている。
【0003】
【発明が解決しようとする課題】
しかしながら、重量平均分子量約25,000〜約60,000の乳酸ポリマーと生理活性物質とを含有し、約5カ月以上にわたり生理活性物質を放出する徐放性製剤は知られていない。
【0004】
【課題を解決するための手段】
本発明は、
(1)重量平均分子量約25,000〜約60,000の乳酸ポリマーと生理活性物質とを含有し、約5カ月以上にわたり生理活性物質を放出する徐放性製剤、
(2)乳酸ポリマーが開環重合により製造したポリ乳酸を加水分解して得られる上記(1)記載の徐放性製剤、
(3)乳酸ポリマーが実質的に触媒を含まない上記(1)記載の徐放性製剤、
(4)乳酸ポリマーが約30,000〜約50,000の重量平均分子量を有する上記(1)記載の徐放性製剤、
(5)乳酸ポリマーが約1.2〜約4.0の分散度を有する上記(1)記載の徐放性製剤、
(6)注射用である上記(1)記載の徐放性製剤、
(7)さらに賦形剤を含有してなる上記(1)記載の徐放性製剤、
(8)賦形剤が糖類である上記(7)記載の徐放性製剤、
(9)生理活性物質が生理活性ペプチドである上記(1)記載の徐放性製剤、
(10)生理活性ペプチドがLHRHアゴニストまたはLHRHアンタゴニストである上記(9)記載の徐放性製剤、
(11)LHRHアゴニストが式
(Pyr)Glu-R1-Trp-Ser-R2-R3-R4-Arg-Pro-R5 (I)
[式中、R1はHis,Tyr,Trpまたはp-NH2-Phe;R2はTyrまたはPhe;R3はGlyまたは置換基を有していてもよいD型のアミノ酸残基;R4はLeu,IleまたはNle;R5はGly-NH-R6(R6は水素原子または水酸基を有しまたは有しないアルキル基)またはNH-R7(R7は水素原子、アミノまたは水酸基を有しまたは有しないアルキル基、またはウレイド)を示す]で表されるペプチドまたはその塩である上記(10)記載の徐放性製剤、
(12)式(I)で表されるペプチドまたはその塩がリュープロレリンまたは酢酸リュープロレリンである上記(11)記載の徐放性製剤、
(13)徐放性製剤中の生理活性物質の含量が約0.01ないし約50%(W/W)である上記(1)記載の徐放性製剤、
(14)乳酸ポリマーに対する生理活性物質の割合が約0.01ないし約50%(w/w)である上記(1)記載の徐放性製剤、
(15)生理活性物質が酢酸リュープロレリンであり、乳酸ポリマーが約28,400〜約47,800の重量平均分子量を有し、約6カ月以上にわたり酢酸リュープロレリンを放出する上記(1)記載の徐放性製剤、および
(16)生理活性物質を含む溶液を内水相とし、重量平均分子量約25,000〜約60,000の乳酸ポリマーを含む溶液を油相とするw/oエマルションをマイクロカプセル化することを特徴とする、約5カ月以上にわたり生理活性物質を放出する徐放性製剤の製造法に関する。
【0005】
本明細書中、重量平均分子量および分散度に関し、前者は、重量平均分子量が120,000、52,000、22,000、9,200、5,050、2,950、1,050、580、162の9種類のポリスチレンを基準物質としたゲルパーミエーションクロマトグラフィー(GPC)で測定したポリスチレン換算の値であり、後者は、この値から算出した値である。測定は、GPCカラムKF804L(昭和電工製、日本)× 2、RIモニター L-3300(日立製作所製、日本)を使用、移動相としてクロロホルムを用いた。
また、アミノ酸および保護基等の略号、本明細書中で用いられる略号は、IUPAC−IUB コミッション・オン・バイオケミカル・ノーメンクレーチュアー(Commission on Biochemical Nomenclature)による略号あるいは当該分野における慣用略号に基づくものとし、また、アミノ酸に関し光学異性体がありうる場合は、特に明示しなければL体を示すものとする。
さらに、本明細書中で使用される略号は次のような意味を示す。
NAcD2Nal :N-アセチル-D-3-(2-ナフチル)アラニル
D4ClPhe :D-3-(4-クロロフェニル)アラニル
D3Pal :D-3-(3-ピリジル)アラニル
NMeTyr :N-メチルチロシル
DLys(Nic):D-(イプシロン-N-ニコチノイル)リシル
Lys(Nisp):(イプシロン-N-イソプロピル)リシル
DhArg(Et2):D-(N,N'-ジエチル)ホモアルギニル
【0006】
本発明で用いられる乳酸ポリマーは、約5カ月以上にわたって生体内で分解し、末端に遊離のカルボキシル基を有する生体内分解性ポリマーである。該ポリマーは、乳酸のホモポリマーである。
本発明の乳酸ポリマーの重量平均分子量は、約25,000〜約60,000、好ましくは約27,000〜約55,000、より好ましくは約28,000〜約50,000であり、このような重量平均分子量を選択することにより、薬物初期バーストが少なく、約5カ月以上にわたり薬物の連続的なゼロ次放出を示す徐放性製剤を製造することができる。本発明で用いられる乳酸ポリマーの分散度(重量平均分子量/数平均分子量)は、好ましくは約1.2〜約4.0、さらに好ましくは約1.5〜約3.5 である。
本発明の乳酸ポリマーは、L-、D-およびDL-体のいずれでもよく、とりわけDL-体が好ましい。該DL-体において、D-体/L-体(モル%)は、好ましくは約75/25ないし約20/80、さらに好ましくは約60/40ないし約25/75、特に好ましくは約55/45ないし約25/75である。
【0007】
本発明で用いられる乳酸ポリマーは、好ましくは乳酸の環状二量体の開環重合反応により製造した原料ポリ乳酸を加水分解することによって製造される。
ここにおいて、開環重合反応により製造した原料ポリ乳酸は、触媒を加えて減圧下に加熱して乳酸を脱水縮合する方法(特開昭56-45920、EP-A 26599)あるいは無触媒下に乳酸を重合して得られる実質的に触媒を含まないポリマーの合成法(特開昭61-28521、EP-A 172636)では得られない高分子領域のポリマーである。開環重合反応(開環重合と略記することもある)は、乳酸の環状二量体を用い、加熱下、触媒を添加して行う方法〔例、ジェイ・エイチ・アール・ウッドランド(J. H. R. Woodland)他、ジャーナル・オブ・メディシナル・ケミストリー(J. Med. Chem.), 16, 897(1973)〕によって行われる。
開環重合により製造したポリ乳酸の重量平均分子量は、加水分解によって得られる乳酸ポリマーの重量平均分子量(約25,000〜約60,000)より大きければ、特に限定されないが、例えば約50,000〜約200,000、好ましくは約60,000〜約100,000である。
上記した開環重合により製造したポリ乳酸としては、一般に入手可能な市販品を用いることができる。
【0008】
本発明で用いられる乳酸ポリマーを得るために行われる、開環重合により製造したポリ乳酸の加水分解は、公知の方法に従い、酸または塩基の存在下に行われる。さらに、加水分解は、水の存在下に行われる。
ここにおいて、酸としては、例えば塩酸,硝酸,硫酸,リン酸などの無機酸、乳酸,酢酸,酒石酸,クエン酸,コハク酸などの有機酸が挙げられる。また、塩基としては、水酸化ナトリウム,水酸化カリウムなどの水酸化アルカリ金属、炭酸ナトリウム,炭酸カリウムなどのアルカリ金属炭酸塩などが挙げられる。塩基の存在下に加水分解を行う場合、塩基の残存量によって、徐放性製剤からの生理活性物質の放出が影響を受けるため、酸の存在下に加水分解を行うことが好ましい。
加水分解は、通常反応に悪影響を及ぼさない溶媒中で行われる。このような溶媒としては、例えばメタノール,エタノール,プロパノールなどのアルコール類、テトラヒドロフラン,ジオキサン,ジエチルエーテル,ジイソプロピルエーテルなどのエーテル類、水、またはこれらの混合溶媒などが挙げられる。また、上記した酸または塩基の過剰量を、溶媒として用いてもよい。
加水分解の際の温度は、例えば約0〜約100℃、好ましくは約10〜約100℃である。
加水分解に要する時間は、開環重合により製造したポリ乳酸の重量平均分子量、酸または塩基の種類、溶媒の種類、温度などによって異なるので、加水分解中にポリ乳酸および乳酸ポリマーの一部を採取し、採取したポリ乳酸および乳酸ポリマーの重量平均分子量を測定することによって適宜決定すればよい。加水分解に要する時間は、特に限定されないが、例えば約1時間〜約10日、好ましくは約10時間〜約5日である。
開環重合により製造したポリ乳酸では、初期バーストの大きな徐放性製剤しか製造できないが、加水分解されたポリ乳酸、すなわち本発明で用いられる乳酸ポリマーでは、初期バーストの小さい徐放性製剤を製造することができる。
【0009】
加水分解されたポリ乳酸は、さらに精製工程に付すことが好ましい。精製工程は、加水分解されたポリ乳酸を有機溶媒に溶解し、得られる溶液を水または水と水溶性有機溶媒との混合溶液中に注入し、沈殿する乳酸ポリマーを分離することにより行われる。
有機溶媒としては、例えばハロゲン化炭化水素類(例、ジクロロメタン,クロロホルム,クロロエタン,ジクロロエタン,トリクロロエタン,四塩化炭素等)、ケトン類(例、アセトン等)、エーテル類(例、テトラヒドロフラン,エチルエーテル,イソプロピルエーテル等)、エステル類(例、酢酸エチル,酢酸ブチル等)、芳香族炭化水素類(例、ベンゼン,トルエン,キシレン等)等が挙げられる。有機溶媒の使用量は、加水分解されたポリ乳酸に対し、例えば約3ないし約20倍量(w/v)である。
水溶性有機溶媒としては、例えばアセトン、メタノール、エタノール、テトラヒドロフラン、アセトニトリル等が挙げられる。水または水と水溶性有機溶媒との混合液の使用量は、特に限定されないが、通常、加水分解されたポリ乳酸に対して大過剰量である。
精製工程における温度は、通常約0ないし約90℃、好ましくは約20ないし約70℃である。
上記した精製工程により、水可溶性の低分子化合物(例えば重量平均分子量約1,000以下のもの)を除去することができる。このような精製工程を経て得られる乳酸ポリマーを用いれば、徐放性製剤を製造する際の生理活性物質の取り込み率(トラップ率)を高めることができ、また、初期バーストの低減された徐放性製剤を製造することができる。
さらに、開環重合により製造したポリ乳酸を加水分解および精製工程に付すことにより、開環重合の際に使用される有害な触媒(例、酸化亜鉛等の亜鉛化合物およびオクタン酸第一スズ等のスズ化合物)等を実質的に含まない乳酸ポリマーを製造することができる。
【0010】
本発明において好適に用いられる生理活性物質としては、特に限定されないが、生理活性ペプチド、抗生物質、抗腫瘍剤、解熱剤、鎮痛剤、消炎剤、鎮咳去痰剤、鎮静剤、筋弛緩剤、抗てんかん剤、抗潰瘍剤、抗うつ剤、抗アレルギー剤、強心剤、不整脈治療剤、血管拡張剤、降圧利尿剤、糖尿病治療剤、抗脂血症剤、抗凝血剤、止血剤、抗結核剤、ホルモン剤、麻薬拮抗剤、骨吸収抑制剤、骨形成促進剤、血管新生阻害剤などが挙げられる。
上記生理活性ペプチドとしては、2個以上のアミノ酸によって構成されるもので分子量約200〜約80,000のものが好ましい。生理活性ペプチドは、好ましくはLHRH(黄体形成ホルモン放出ホルモン)アゴニストまたはLHRHアンタゴニストである。
LHRHアゴニストとしては、例えば
式: (Pyr)Glu-R1-Trp-Ser-R2-R3-R4-Arg-Pro-R5 (I)
[式中、R1はHis,Tyr,Trpまたはp-NH2-Phe;R2はTyrまたはPhe;R3はGlyまたは置換基を有していてもよいD型のアミノ酸残基;R4はLeu,IleまたはNle;R5はGly-NH-R6(R6は水素原子または水酸基を有しまたは有しないアルキル基)またはNH-R7(R7は水素原子、アミノまたは水酸基を有しまたは有しないアルキル基、またはウレイド(-NH-CO-NH2))を示す]で表されるペプチドまたはその塩が挙げられる。
【0011】
上記式(I)中、R3におけるD型のアミノ酸残基としては、例えば炭素数が9までのα-D-アミノ酸(例、D-Leu,Ile,Nle,Val,Nval,Abu,Phe,Phg,Ser,Thr,Met,Ala,Trp,α−Aibu)などが挙げられる。また、R3における置換基としては、例えばtert-ブチル、tert-ブトキシ、tert-ブトキシカルボニル、メチル、ジメチル、トリメチル、2-ナフチル、インドリル-3-イル、2-メチルインドリル、ベンジル-イミダゾ-2-イル等が挙げられる。
式(I)中、R6またはR7におけるアルキル基としては、例えばC1-4アルキル基が好ましく、その例としては、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec-ブチル、tert-ブチルが挙げられる。
また、式(I)で表されるペプチド〔以下、ペプチド(I)と略記することがある〕の塩としては、例えば酸塩(例、炭酸塩、重炭酸塩、酢酸塩、トリフルオロ酢酸塩、プロピオン酸塩、コハク酸塩等),金属錯体化合物(例、銅錯体、亜鉛錯体等)が挙げられる。
ペプチド(I)またはその塩は、例えば米国特許第3,853,837号,同第4,008,209号,同第3,972,859号,英国特許第1,423,083号,プロシーデイングス・オブ・ザ・ナショナル・アカデミー・オブ・サイエンス・オブ・ジ・ユナイテッド・ステイツ・オブ・アメリカ(Proceedings of the National Academy of Sciences of the United States of America)第78巻,第6509〜6512頁(1981年)等に記載の方法あるいはこれに準ずる方法により製造することができる。
【0012】
ペプチド(I)は、好ましくは下記の式(a)〜(j)のいずれかである。
(a)リュープロレリン〔Leuprorelin、式(I)においてR1=His,R2=Tyr,R3=D-Leu,R4=Leu,R5=NHCH2-CH3であるペプチド〕;(b)ゴナドレリン(Gonadrelin)
【化1】
〔ドイツ特許第2213737号〕;(c)ブセレリン(Buserelin)
【化2】
〔米国特許第4024248号、ドイツ特許第2438352号、特開昭51-41359号〕;(d)トリプトレリン(Triptorelin)
【化3】
〔米国特許第4010125号、特開昭52-31073号〕;(e)ゴセレリン(Goserelin)
【化4】
〔米国特許第4100274号、特開昭52-136172号〕;(f)ナファレリン(Nafarelin)
【化5】
〔米国特許第4234571号、特開昭55-164663号、特開昭63-264498号、特開昭64-25794号〕;(g)ヒストレリン(Histrelin)
【化6】
;(h)デスロレリン(Deslorelin)
【化7】
〔米国特許第4569967号、米国特許第4218439号〕;(i)メテレリン(Meterelin)
【化8】
〔WO9118016〕;(j)レシレリン(Lecirelin)
【化9】
〔ベルギー特許第897455号、特開昭59-59654号〕等が挙げられる。
上記した式(c)〜(j)において、式(I)のR3に相当するアミノ酸はD−体である。
ペプチド(I)またはその塩は、特に好ましくはリュープロレリンまたは酢酸リュープロレリンである。ここにおいて、酢酸リュープロレリンとは、リュープロレリンの酢酸塩である。
【0013】
LHRHアンタゴニストとしては、例えば米国特許第4,086,219号,同第4,124,577号,同第4,253,997号,同第4,317,815号で開示されたもの、あるいは式:
【化10】
〔式中、Xは水素またはテトラヒドロフリルカルボキサミドを、Qは水素またはメチルを、AはニコチノイルまたはN,N'-ジエチルアミジノを、BはイソプロピルまたはN,N'-ジエチルアミジノを示す〕で表されるペプチド〔以下、ペプチド(II)と略記することがある〕またはその塩が挙げられる。
式(II)において、Xは好ましくはテトラヒドロフリルカルボキサミド、さらに好ましくは(2S)-テトラヒドロフリルカルボキサミドである。また、Aは好ましくはニコチノイルである。Bは好ましくはイソプロピルである。
また、ペプチド(II)が1種以上の不斉炭素原子を有する場合、2種以上の光学異性体が存在する。ペプチド(II)は、このような光学異性体として、またはこれら光学異性体の混合物として用いてもよい。
【0014】
ペプチド(II)の塩としては、好ましくは、薬理学的に許容される塩が用いられる。このような塩としては、無機酸(例、塩酸,硫酸,硝酸など),有機酸(例、炭酸,重炭酸,コハク酸,酢酸,プロピオン酸,トリフルオロ酢酸など)などとの塩が挙げられる。ペプチド(II)の塩は、さらに好ましくは有機酸(例、炭酸,重炭酸,コハク酸,酢酸,プロピオン酸,トリフルオロ酢酸など)との塩である。ペプチド(II)の塩は、特に好ましくは酢酸との塩である。これらの塩は、モノないしトリ塩のいずれであってもよい。
【0015】
ペプチド(II)またはその塩は、好ましくは下記の式(1)〜(4)である。
【化11】
〔式中、mは1ないし3の実数を示す〕
(3)NAcD2Nal-D4ClPhe-D3Pal-Ser-Tyr-DhArg(Et2)-Leu-hArg(Et2)-Pro-DAlaNH2
(4)NAcD2Nal-D4ClPhe-D3Pal-Ser-Tyr-DhArg(Et2)-Leu-hArg(Et2)-Pro-DAlaNH2・n(CH3COOH)
〔式中、nは1ないし3の実数を示す〕
上記した式(2)および(4)は、塩または溶媒和物を示す。
ペプチド(II)またはその塩は、さらに好ましくは上記(1)または(2)であり、特にこれらはS−アイソマーであることが好ましい。以下、上記(1)のS−アイソマーをペプチドA1と略記する。
【0016】
ペプチド(II)またはその塩は、自体公知の方法、例えば特開平3-101695(EP-A 413209)、ジャーナル・オブ・メディシナル・ケミストリー(Journal of Medicinal Chemistry)、35巻、3942頁、(1992)などに記載の方法あるいはこれに類する方法により製造できる。
【0017】
本発明において好適に用いられる生理活性ペプチドとしては、さらに例えばインスリン,ソマトスタチン,ソマトスタチン誘導体(サンドスタチン,米国特許第4,087,390号,同第4, 093,574号,同第4,100,117号,同第4,253,998号参照),成長ホルモン,プロラクチン,副腎皮質刺激ホルモン(ACTH),ACTH誘導体(エビラタイドなど),メラノサイト刺激ホルモン(MSH),甲状腺ホルモン放出ホルモン〔(Pyr)Glu-His-ProNH2 の構造式で表わされ、以下TRHと略記することもある〕その塩およびその誘導体(特開昭50-121273号,特開昭52-116465号公報参照),甲状腺刺激ホルモン(TSH),黄体形成ホルモン(LH),卵胞刺激ホルモン(FSH),バソプレシン,バソプレシン誘導体{デスモプレシン〔日本内分泌学会雑誌,第54巻第5号第676〜691頁(1978)〕参照},オキシトシン,カルシトニン,副甲状腺ホルモン(PTH),グルカゴン,ガストリン,セクレチン,パンクレオザイミン,コレシストキニン,アンジオテンシン,ヒト胎盤ラクトーゲン,ヒト絨毛性ゴナドトロピン(HCG),エンケファリン,エンケファリン誘導体〔米国特許第4,277,394号,ヨーロッパ特許出願公開第31567号公報参照〕,エンドルフィン,キョウトルフィン,インターフェロン類(例、α型,β型,γ型等),インターロイキン類(例、1,2,3,4,5,6,7,8,9,10,11,12等),タフトシン,サイモポイエチン,サイモシン,サイモスチムリン,胸腺液性因子(THF),血中胸腺因子(FTS)およびその誘導体(米国特許第4,229,438号参照),およびその他の胸腺因子〔医学のあゆみ,第125巻,第10号,835−843頁(1983年)〕,腫瘍壊死因子(TNF),コロニー誘発因子(CSF,GCSF,GMCSF,MCSF等),モチリン,ダイノルフィン,ボンベシン,ニューロテンシン,セルレイン,ブラディキニン,ウロキナーゼ,アスパラギナーゼ,カリクレイン,サブスタンスP,インスリン様成長因子(IGF−I,IGF−II),神経成長因子(NGF),細胞増殖因子(EGF,TGF−α,TGF−β,PDGF,酸性FGF,塩基性FGF等),骨形成因子(BMP),神経栄養因子(NT−3,NT−4,CNTF,GDNF,BDNF等),血液凝固因子の第VIII因子,第IX因子,塩化リゾチーム,ポリミキシンB,コリスチン,グラミシジン,バシトラシンおよびエリスロポエチン(EPO),トロンボポエチン(TPO),エンドセリン拮抗作用を有するペプチド類(ヨーロッパ特許公開第436189号,同第457195号,同第496452号,特開平3-94692号,同3-130299号公報参照)などが挙げられる。
【0018】
抗生物質としては、例えばゲンタマイシン,ジベカシン,カネンドマイシン,リビドマイシン,トブラマイシン,アミカシン,フラジオマイシン,シソマイシン,塩酸テトラサイクリン,塩酸オキシテトラサイクリン,ロリテトラサイクリン,塩酸ドキシサイクリン,アンピシリン,ピペラシリン,チカルシリン,セファロチン,セファロリジン,セフォチアム,セフスロジン,セフメノキシム,セフメタゾール,セファゾリン,セフォタキシム,セフォペラゾン,セフチゾキシム,モキサラクタム,チエナマイシン,スルファゼシン,アズスレオナムなどが挙げられる。
抗腫瘍剤としては、例えばブレオマイシン,メソトレキセート,アクチノマイシンD,マイトマイシンC,硫酸ビンブラスチン,硫酸ビンクリスチン,ダウノルビシン,アドリアマイシン,ネオカルチノスタチン,シトシンアラビノシド,フルオロウラシル,テトラヒドロフリル−5−フルオロウラシル,クレスチン,ピシバニール,レンチナン,レバミゾール,ベスタチン,アジメキソン,グリチルリチン,ポリI:C,ポリA:U,ポリICLCなどが挙げられる。
【0019】
解熱,鎮痛,消炎剤としては、例えばサリチル酸,スルピリン,フルフェナム酸,ジクロフェナック,インドメタシン,モルヒネ,塩酸ペチジン,酒石酸レボルファノール,オキシモルフォンなどが挙げられる。
鎮咳去痰剤としては、例えば塩酸エフェドリン,塩酸メチルエフェドリン,塩酸ノスカピン,リン酸コデイン,リン酸ジヒドロコデイン,塩酸アロクラマイド,塩酸クロフェダノール,塩酸ピコペリダミン,クロペラスチン,塩酸プロトキロール,塩酸イソプロテレノール,硫酸サルブタモール,硫酸テルブタリンなどが挙げられる。
鎮静剤としては、例えばクロルプロマジン,プロクロルペラジン,トリフロペラジン,硫酸アトロピン,臭化メチルスコポラミンなどが挙げられる。
筋弛緩剤としては、例えばメタンスルホン酸プリジノール,塩化ツボクラリン,臭化パンクロニウムなどが挙げられる。
抗てんかん剤としては、例えばフェニトイン,エトサクシミド,アセタゾラミドナトリウム,クロルジアゼポキシドなどが挙げられる。
抗潰瘍剤としては、例えばメトクロプロミド,塩酸ヒスチジンなどがなどが挙げられる。
抗うつ剤としては、イミプラミン,クロミプラミン,ノキシプチリン,硫酸フェネルジンなどが挙げられる。
【0020】
抗アレルギー剤としては、例えば塩酸ジフェンヒドラミン,マレイン酸クロルフェニラミン,塩酸トリペレナミン,塩酸メトジラジン,塩酸クレミゾール,塩酸ジフェニルピラリン,塩酸メトキシフェナミンなどが挙げられる。
強心剤としては、例えばトランスパイオキソカンファー,テオフィロール,アミノフィリン,塩酸エチレフリンなどが挙げられる。
不整脈治療剤としては、例えばプロプラノール,アルプレノロール,ブフェトロール,オキシプレノロールなどが挙げられる。
血管拡張剤としては、例えば塩酸オキシフェドリン,ジルチアゼム,塩酸トラゾリン,ヘキソベンジン,硫酸バメタンなどが挙げられる。
降圧利尿剤としては、例えばヘキサメトニウムブロミド,ペントリニウム,塩酸メカミルアミン,塩酸エカラジン,クロニジンなどが挙げられる。
糖尿病治療剤としては、例えばグリミジンナトリウム,グリピザイド,塩酸フェンフォルミン,塩酸ブフォルミン,メトフォルミンなどが挙げられる。
抗脂血症剤としては、例えばプラバスタチンナトリウム,シンバスタチン,クリノフィブラート,クロフィブラート,シンフィブラート,ベザフィブラートなどが挙げられる。
【0021】
抗凝血剤としては、例えばヘパリンナトリウムなどが挙げられる。
止血剤としては、例えばトロンボプラスチン,トロンビン,メナジオン亜硫酸水素ナトリウム,アセトメナフトン,ε−アミノカプロン酸,トラネキサム酸,カルバゾクロムスルホン酸ナトリウム,アドレノクロムモノアミノグアニジンメタンスルホン酸塩などが挙げられる。
抗結核剤としては、例えばイソニアジド,エタンブトール,パラアミノサリチル酸などが挙げられる。
ホルモン剤としては、例えばプレドニゾロン,リン酸ナトリウムプレドニゾロン,デキサメタゾン硫酸ナトリウム,ベタメタゾンリン酸ナトリウム,リン酸ヘキセストロール,酢酸ヘキセストロール,メチマゾールなどが挙げられる。
麻薬拮抗剤としては、例えば酒石酸レバロルファン,塩酸ナロルフィン,塩酸ナロキソンなどが挙げられる。
骨吸収抑制剤としては、例えばイプリフラボン,アレンドロネート,リセドロネートなどが挙げられる。
骨形成促進剤としては、例えばBMP,PTH,TGF−β,IGF−1などのポリペプチド以外に(2R,4S)-(-)-N-[4-(ジエトキシホスホリルメチル)フェニル]-1,2,4,5-テトラヒドロ-4-メチル-7,8-メチレンジオキシ-5-オキソ-3-ベンゾチエピン-2-カルボキサミド,2-(3-ピリジル)-エタン-1,1-ジフォスフォン酸,ラロキシフェンなどが挙げられる。
血管新生抑制剤としては、例えば血管新生抑制ステロイド〔サイエンス(Science)第221巻719頁(1983年)参照〕,フマギリン(ヨーロッパ特許公開第325199号公報参照),フマギロール誘導体(ヨーロッパ特許公開第357061号,同第359036号,同第386667号,同第415294号公報参照),バチマスタットなどが挙げられる。
【0022】
生理活性物質は、それ自身であっても薬理学的に許容される塩として用いてもよい。例えば、生理活性物質がアミノ基等の塩基性基を有する場合、無機酸(例、塩酸,硫酸,硝酸等)または有機酸(例、炭酸,コハク酸等)との塩が用いられる。また、生理活性物質がカルボキシ基等の酸性基を有する場合、無機塩基(例、ナトリウム,カリウム等のアルカリ金属等)または有機塩基(例、トリエチルアミン等の有機アミン類、アルギニン等の塩基性アミノ酸類等)との塩が用いられる。
【0023】
本発明の徐放性製剤に用いられる生理活性物質は、好ましくは生理活性ペプチド、さらに好ましくはLHRHアゴニストまたはLHRHアンタゴニストである。該生理活性物質は、特に好ましくはLHRHアゴニストであり、とりわけペプチド(I)またはその塩が好ましい。
【0024】
徐放性製剤中の生理活性物質の含量は、生理活性物質の種類、所望の薬理効果および効果の持続期間などによって異なるが、例えば約0.01ないし約50%(W/W)、好ましくは約0.1ないし約30%(W/W)である。
【0025】
本発明の徐放性製剤は、生理活性物質と乳酸ポリマーとを含有する微粒子(すなわちマイクロスフェア)を含有していればよい。該微粒子(すなわちマイクロスフェア)の具体例としては、例えば1個の粒子中に1個の生理活性物質コアーを含有するマイクロカプセル、1個の粒子中に多数の生理活性物質コアーを含有する多核マイクロカプセル、または分子状で生理活性物質が固溶体として乳酸ポリマーに溶解あるいは分散しているような細粒子などが挙げられる。
【0026】
本発明の徐放性製剤の好適な例としては、生理活性物質が酢酸リュープロレリンであり、乳酸ポリマーが約28,400〜約47,800の重量平均分子量を有し、約6カ月以上にわたり酢酸リュープロレリンを放出する徐放性製剤が挙げられる。
【0027】
本発明の徐放性製剤は、例えば生理活性物質を含む溶液を内水相とし、乳酸ポリマーを含む溶液を油相とするW/Oエマルションをマイクロカプセル化することにより製造される。該マイクロカプセル化は、例えば水中乾燥法、相分離法、噴霧乾燥法またはこれらに準ずる方法によって行われる。
生理活性物質を含む溶液を内水相とし、本発明の乳酸ポリマーを含む溶液を油相とするW/Oエマルションは、以下のようにして製造することができる。
まず、水に生理活性物質を、約0.001〜約90%(w/w)、好ましくは約0.01〜約80%(w/w)の濃度になるように溶解し、内水相とする。該内水相には、マイクロカプセルへの生理活性物質の取り込み率を向上させるために、ゼラチン、寒天、アルギン酸ナトリウム、ポリビニールアルコール、あるいは塩基性アミノ酸(例、アルギニン、リジンなど)などの薬物保持物質を加えてもよい。該薬物保持物質の添加量は、生理活性物質に対して、通常約0.01〜約100重量倍、より好ましくは約0.05〜約50重量倍である。これらの薬物保持物質は、あらかじめ任意の濃度に生理活性物質と共に水に溶解し、除菌・除塵フィルターを用いてろ過した後、凍結乾燥して保存し、調製時に溶解して用いることもできる。
なお、本発明の徐放性製剤においては、内水相に薬物保持物質を用いない場合でも、生理活性物質の取り込み率が十分満足なものである。
【0028】
また、内水相には、生理活性物質の安定性、溶解性を保つためのpH調整剤として、炭酸、酢酸、シュウ酸、クエン酸、リン酸、塩酸、水酸化ナトリウム、アルギニン、リジンおよびそれらの塩などを添加してもよい。さらに、生理活性物質の安定化剤として、アルブミン、ゼラチン、トレハロース、クエン酸、エチレンジアミン四酢酸ナトリウム、デキストリン、シクロデキストリン(α−,β−,γ−)およびそれらの誘導体(例、マルトシールβ−シクロデキストリン,β−シクロデキストリンスルフォブチルエーテルなど)、亜硫酸水素ナトリウム、ポリエチレングリコールなどのポリオール化合物、ポリオキシエチレンソルビタン脂肪酸エステル[例、Tween 80,Tween 60(花王、日本)]、ポリオキシエチレンヒマシ油誘導体[例、HCO-60,HCO-70(日光ケミカルズ、日本)]などの界面活性剤、パラオキシ安息香酸エステル類(例、メチルパラベン、プロピルパラベンなど)、ベンジルアルコール、クロロブタノール、チメロサールなどを添加してもよい。
【0029】
このようにして得られる内水相と、乳酸ポリマーを含む溶液(油相)とを混合し、得られる混合物を乳化工程に付し、W/Oエマルションを調製する。
乳酸ポリマーを含む溶液(油相)としては、乳酸ポリマーを有機溶媒に溶解したものが用いられる。該有機溶媒としては、沸点が約120℃以下、疎水性で、乳酸ポリマーを溶解するものであればよく、例えばハロゲン化炭化水素類(例、ジクロロメタン、クロロホルム、クロロエタン、ジクロロエタン、トリクロロエタン、四塩化炭素など)、脂肪酸エステル類(例、酢酸エチル、酢酸ブチルなど)、エーテル類(例、エチルエーテル、イソプロピルエーテルなど)、芳香族炭化水素類(例、ベンゼン、トルエン、キシレンなど)などが挙げられる。また、これらの有機溶媒の2種以上を適宜の割合で混合して用いてもよい。有機溶媒は、好ましくはハロゲン化炭化水素類、特に好ましくはジクロロメタンである。
有機溶媒中の乳酸ポリマーの濃度は、乳酸ポリマーの種類、分子量、有機溶媒の種類により異なるが、通常約0.01〜約90%(w/w)、好ましくは約0.1〜約80%(w/w)である。
なお、内水相との相溶性、外水相への有機溶媒の分配、揮散などを変化させるため、油相に一部親水性の有機溶媒、例えばエタノール、アセトニトリル、アセトン、テトラヒドロフランなどを添加してもよい。また、内部の生理活性物質を溶解あるいは安定化させるために、ショ糖脂肪酸エステルなどの界面活性剤を添加してもよい。
このようにして得られる油相は、通常フィルターで除菌・除塵ろ過して用いる。また、乳酸ポリマーの安定性に依存するが、乳酸ポリマーを含む溶液を室温ないし冷所で密閉容器の中で保存してもよい。
【0030】
生理活性物質の水溶液と乳酸ポリマーの有機溶媒溶液との混合割合は、前者1重量部当たり、後者が約0.1〜約1000重量部、好ましくは約1〜約100重量部である。また、生理活性物質の種類、所望の薬理効果および効果の持続期間などにより異なるが、乳酸ポリマーに対する生理活性物質の割合が、約0.01ないし約50%(w/w)、好ましくは約0.5ないし約40%(w/w)、特に好ましくは約0.1ないし約30%(w/w)であるように混合するのが良い。
【0031】
乳化工程は、公知の分散法、例えば断続振とう法、プロペラ型攪拌機あるいはタービン型攪拌機などの攪拌機による方法、コロイドミル法、ホモジナイザー法、超音波照射法などにより行われる。このW/Oエマルションは、その乳化の程度で生理活性物質の放出が影響を受け、乳化の程度が不十分であると初期バーストが大きくなる傾向にあり、内水相がある程度以上に微細な程、生理活性物質と乳酸ポリマーの相互作用が強く、乳酸ポリマーによる放出制御が乳酸ポリマーの生分解性に依存して長期の放出制御をより正確にできるので好ましい。
【0032】
ついで、このようにして得られるW/Oエマルションをマイクロカプセル化工程に付す。
例えば水中乾燥法によりマイクロカプセル化を行う場合、W/Oエマルションをさらに水相(以下、外水相と略記する)に加え、W/O/Wエマルションを製造した後、油相中の有機溶媒を除去し、マイクロカプセルを調製する。
上記外水相中に乳化剤を加えてもよい。該乳化剤としては、一般に安定なO/Wエマルションを形成するものであればいずれでもよいが、例えばアニオン界面活性剤(例、オレイン酸ナトリウム、ステアリン酸ナトリウム、ラウリル硫酸ナトリウムなど)、非イオン性界面活性剤(例、Tween 80、Tween 60、HCO-60、HCO-70など)、ポリビニールアルコール、ポリビニールピロリドン、ゼラチンなどが挙げられる。これらの乳化剤は、2種以上を適宜の割合で混合して用いてもよい。外水相における乳化剤の濃度は、例えば約0.01ないし約20%、好ましくは約0.05ないし約10%である。
有機溶媒の除去は、公知の方法に従って行えばよい。このような方法としては、例えばプロペラ型攪拌機あるいはマグネチックスターラーなどで攪拌しながら、常圧下もしくは徐々に減圧して溶媒を除去する方法、ロータリーエバポレーターなどを用いて、真空度、温度を調節しながら溶媒を除去する方法等が挙げられる。
このようにして得られるマイクロカプセルを、遠心分離あるいはろ過により分取した後、蒸留水で数回繰り返し洗浄して、マイクロカプセルの表面に付着している遊離の生理活性物質、薬物保持物質、乳化剤等を除去する。ついで、洗浄されたマイクロカプセルを、減圧乾燥するか、あるいは蒸留水に再分散後凍結乾燥して、さらに有機溶媒の除去を行う。
【0033】
相分離法によりマイクロカプセル化を行う場合、攪拌下、W/Oエマルションにコアセルベーション剤を徐々に加え、乳酸ポリマーを析出、固化させることにより、マイクロカプセルを調製する。
コアセルベーション剤としては、乳酸ポリマーの溶剤に混和する高分子系、鉱物油系または植物油系の化合物で、カプセル化用の乳酸ポリマーを溶解しないものであればよく、例えばシリコン油、ゴマ油、大豆油、コーン油、綿実油、ココナッツ油、アマニ油、鉱物油、n-ヘキサン、n-ヘプタンなどが挙げられる。これらは2種以上を混合して用いてもよい。コアセルベーション剤の使用量は、W/Oエマルションに対し、例えば約0.01倍ないし約1,000容量倍、好ましくは約0.1ないし約200容量倍である。
このようにして得られるマイクロカプセルを、遠心分離あるいはろ過により分取した後、ヘキサン,ヘプタンなどの洗浄液で繰り返し洗浄して、コアセルベーション剤を除去し、その後、加温ないし減圧して洗浄液を蒸発させる。さらに、所望により、上記した水中乾燥法の場合と同様にして、遊離の生理活性物質および有機溶媒の除去を行う。
【0034】
噴霧乾燥法によりマイクロカプセル化を行う場合、W/Oエマルションまたは水中乾燥法の場合と同様にして製造したW/O/Wエマルションを、ノズルを用いてスプレードライヤー装置(噴霧乾燥機)の乾燥室内へ噴霧し、極めて短時間に微粒化液滴内の有機溶媒および水を揮発させることにより、微粒状のマイクロカプセルを調製する。ノズルとしては、例えば二液体ノズル型、圧力ノズル型、回転ディスク型が挙げられる。
このようにして得られるマイクロカプセルを、所望により、蒸留水で数回繰り返し洗浄して、マイクロカプセルの表面に付着している遊離の生理活性物質、薬物保持物質、乳化剤等を除去する。ついで、洗浄されたマイクロカプセルを、減圧乾燥するか、あるいは蒸留水に再分散後凍結乾燥して、さらに有機溶媒の除去を行ってもよい。
【0035】
また、生理活性物質が、1)一種の疎水性有機溶媒(例、ジクロロメタン、クロロホルム、ジクロロエタン、四塩化炭素、酢酸エチル、シクロヘキサンなど)と少なくとも一種の親水性有機溶媒(例、メタノール、エタノール、アセトニトリルなど)からなる油相に溶解する場合、2)ポリマーと疎水性有機溶媒の溶液からなる油相に溶解する場合、または3)前記疎水性有機溶媒に少なくとも一種の界面活性剤(例、グリセリン脂肪酸エステル、プロピレングリコール脂肪酸エステル、ショ糖脂肪酸エステルなど)を添加してなる油相に溶解する場合、これらの油相を、前記水中乾燥法で用いた外水相に分散し、O/Wエマルションを形成させた後、前記水中乾燥法の場合と同様にして油相中の有機溶媒を除去し、マイクロカプセルを調製することもできる。さらに、該O/Wエマルションを、上記した相分離法または噴霧乾燥法に付してマイクロカプセルを調製することもできる。
【0036】
本発明の徐放性製剤は、賦形剤を含有していることが好ましい。該賦形剤としては、生体内に投与しても毒性が少なく、凍結乾燥または噴霧乾燥などの乾燥が容易で、生体内に投与した場合速やかに溶解するか、また、用時溶解するものであることが望まれる。このような賦形剤としては、例えば糖、セルロース誘導体、アミノ酸、タンパク質、ポリアクリル酸誘導体、有機塩、無機塩などが挙げられる。これらの賦形剤は、2種以上を適宜の割合で混合して用いてもよい。
ここにおいて、糖としては、例えばD-マンニトール、アルギン酸ナトリウム、果糖、デキストラン、デキストリン、白糖、D-ソルビトール、ラクトース、ブドウ糖、マルトース、デンプン類、トレハロースなどが挙げられる。
セルロース誘導体としては、例えばカルボキシメチルセルロース、ヒドロキシプロピルメチルセルロース、エチルセルロース、ヒドロキシメチルセルロース、ヒドロキシプロピルセルロース、セルロースアセテートフタレート、ヒドロキシプロピルメチルセルロースフタレート、ヒドロキシメチルセルロースアセテートサクシネートなどが挙げられる。
アミノ酸としては、例えばグリシン、アラニン、チロシン、アルギニン、リジンなどが挙げられる。
タンパク質としては、例えばゼラチン、フィブリン、コラーゲン、アルブミンなどが挙げられる。
ポリアクリル酸誘導体としては、例えばポリアクリル酸ナトリウム、メタアクリル酸/アクリル酸共重合体(オイドラギット、ローム社製、ドイツ)などが挙げられる。
有機塩としては、例えばクエン酸ナトリウム、酒石酸ナトリウム、炭酸ナトリウム、炭酸カリウムなどが挙げられる。
無機塩としては、例えば塩化ナトリウム、塩化カリウム、リン酸ナトリウム、リン酸カリウムなどが挙げられる。
賦形剤としては、上記以外に、徐放性製剤用基剤であるポリマーを溶解しない水溶性ポリマー、例えばポリビニールピロリドン、ポリビニールアルコールなども用いられる。
賦形剤は、好ましくは糖類であり、とりわけ凍結乾燥が容易で毒性が少ないD-マンニトールが好ましい。
【0037】
賦形剤の使用量は、賦形剤の溶解度、賦形剤を溶解して得られる溶液の張度,粘度,分散性,安定性などによって決定されるが、徐放性製剤を乾燥した場合に、乾燥徐放性製剤中の賦形剤の含量が、例えば約0.5から約99%(w/w)、好ましくは約1から約90%(w/w)、より好ましくは約2から約60%(w/w)となるように用いられる。賦形剤としてD-マンニトールを用いる場合は、乾燥徐放性製剤中の賦形剤の含量が、約2から約40%(w/w)となることが特に好ましい。
これらの賦形剤の添加によって、1)徐放性製剤(特にマイクロスフェア)の乾燥時および乾燥後の粒子の接触および衝突の頻度が低下し、凍結乾燥または噴霧乾燥時の粒子の均一性が保たれる、2)徐放性製剤のガラス転移点以上の温度での乾燥が可能となり、より完全な水または有機溶媒の除去が可能となる、3)徐放性製剤の経時的安定性が改善され、分散性が良好で、冷所保存に限定されることなく、例えば室温での長期使用期限を有する徐放性製剤が得られるなどの優れた効果が得られる。
【0038】
本発明において、賦形剤を含有する徐放性製剤は、例えば上記した水中乾燥法、相分離法または噴霧乾燥法によって得られるマイクロカプセルと、賦形剤とを混合することによって製造することができる。該マイクロカプセルは、洗浄後に減圧乾燥したもの、あるいは洗浄後に蒸留水に再分散し凍結乾燥したものであってもよい。混合の方法は、特に限定されず、例えば混合機などを用いて行われるが、均一な混合物を得られるような方法が好ましい。
また、賦形剤を含有する徐放性製剤は、例えば噴霧乾燥法によりマイクロカプセルを製造する場合に、W/Oエマルションの噴霧と同時に賦形剤の水溶液を別ノズルから噴霧することによっても製造することができる。
さらに、賦形剤を含有する徐放性製剤は、水中乾燥法および噴霧乾燥法において用いられるW/O/Wエマルションを製造する際に、外水相に賦形剤の水溶液を使用することによっても製造することができる。
賦形剤を含有する徐放性製剤は、好ましくは水中乾燥法、相分離法または噴霧乾燥法によって得られるマイクロカプセルを洗浄し、洗浄されたマイクロカプセルを、賦形剤を溶解または懸濁した蒸留水に分散し、ついで凍結乾燥または減圧乾燥することによって製造される。また、洗浄されたマイクロカプセルを蒸留水に分散し、得られる分散液に賦形剤を溶解または懸濁した後に、凍結乾燥または減圧乾燥を行ってもよい。とりわけ、洗浄されたマイクロカプセルを賦形剤を溶解した蒸留水に分散するか、洗浄されたマイクロカプセルを蒸留水に分散して得られる分散液に賦形剤を溶解した後に、凍結乾燥することにより、均一な混合物が得られる。
【0039】
さらに、上記した水中乾燥法、相分離法または噴霧乾燥法によって得られるマイクロカプセルを、所望により、基剤として用いたポリマーのガラス転移温度 (Tg) 以上で、該マイクロカプセルの各粒子が互いに付着しない程度の温度に加熱することより、マイクロカプセル中の水および有機溶媒の除去をより完全に行うとともに、徐放性の改善を行うことができる。この際、有機溶媒は、約1000ppm 未満、好ましくは約500ppm 未満、より好ましくは約100ppm 未満程度まで除去することが好ましい。
ガラス転移温度とは、示差走査熱量計(DSC)を用い、加温速度を毎分10または20℃で昇温した際に得られる中間点ガラス転移温度を言う。
加熱の時期は、所望により賦形剤を添加した後、マイクロカプセルを凍結乾燥または減圧乾燥した後が好ましいが、特に限定されるものではなく、例えば小分け後でもよい。
【0040】
加熱温度が基剤として用いたポリマーのガラス転移温度未満では、水または有機溶媒の除去が充分でない場合があり、また高温過ぎるとマイクロカプセルの融着,変形,生理活性物質の分解,劣化等の危険性が増大するので、加熱温度は一概に定義できないが、基剤として用いたポリマーの物性(例、分子量,安定性等),生理活性物質,マイクロカプセルの平均粒子径,加熱時間,マイクロカプセルの乾燥程度,加熱方法等を考慮し、適宜決定することができる。
加熱温度は、好ましくは基剤として用いたポリマーのガラス転移温度からガラス転移温度より約30℃高い温度以下の温度、さらに好ましくはポリマーのガラス転移温度からガラス転移温度より約20℃高い温度以下の温度である。
【0041】
加熱時間は、加熱温度,処理するマイクロカプセル量などによって異なるが、一般的にはマイクロカプセル自体の温度が所定の温度に達した後、約6〜約120時間、さらに好ましくは約12〜約96時間である。また、加熱時間の上限は、残存有機溶媒、水分が許容値以下になれば特に限定されないが、ガラス転移温度以上の条件下ではマイクロカプセルが軟化し、マイクロカプセル同志の物理的接触あるいはマイクロカプセル積層時の荷重により変形するので、有機溶媒、水分の残存が許容値以下になったら、速やかに加熱を終了することが好ましい。
加熱方法は特に限定されないが、マイクロカプセルが均一に加熱される方法であればいかなる方法を用いてもよい。該加熱方法の好ましい具体例として、例えば凍結乾燥機、減圧恒温機等で減圧下に加熱乾燥する方法等が挙げられる。
【0042】
本発明の徐放性製剤は、例えば注射剤、埋め込み剤、経口投与製剤(例、散剤、顆粒剤、カプセル剤、錠剤、シロップ剤、乳剤、懸濁剤等)、経鼻投与製剤、坐剤(例、直腸坐剤、膣坐剤など)等のいずれであってもよい。これらの製剤は、製剤分野において通常一般に用いられる公知の方法によって製造することができる。
例えば注射剤は、上記したマイクロカプセルを、水性あるいは油性の分散媒に分散することにより製造される。水性分散媒としては、例えば蒸留水に等張化剤(例、塩化ナトリウム、ブドウ糖、D-マンニトール、ソルビトール、グリセリンなど)、分散剤(例、Tween 80、HCO-50、HCO-60、カルボキシメチルセルロース、アルギン酸ナトリウムなど)、保存剤(例、ベンジルアルコール、塩化ベンザルコニウム、フェノールなど)、無痛化剤(例、ブドウ糖、グルコン酸カルシウム、塩酸プロカインなど)などを溶解した溶液が挙げられる。また、油性分散媒としては、例えばオリーブ油、ゴマ油、ラッカセイ油、大豆油、コーン油、中鎖脂肪酸グリセリドなどが挙げられる。
該注射剤は、プレフィルドシリンジのチャンバー内に充填されてもよいし、また、分散媒とマイクロカプセルをいわゆるダブルチャンバープレフィルドシリンジ(DPS)内の異なるチャンバーに分離して充填してもよい。
また、注射剤を製造する際、マイクロカプセルに、上記の組成以外に、さらに、賦形剤(例、マンニトール、ソルビトール、ラクトース、ブドウ糖など)を加えて、再分散した後、凍結乾燥もしくは噴霧乾燥して固型化し、用時に、注射用蒸留水あるいは適当な分散媒を加えると、より安定した徐放性注射剤が得られる。
【0043】
経口投与製剤は、例えば上記したマイクロカプセルに、賦形剤(例、乳糖、白糖、デンプンなど)、崩壊剤(例、デンプン、炭酸カルシウムなど)、結合剤(例、デンプン、アラビアゴム、カルボキシメチルセルロース、ポリビニールピロリドン、ヒドロキシプロピルセルロースなど)、滑沢剤(例、タルク、ステアリン酸マグネシウム、ポリエチレングリコール6000など)などを添加して圧縮成形し、次いで必要により、味のマスキング,腸溶性あるいは持続性の目的のため自体公知の方法でコーティングすることにより製造できる。コーティング剤としては、例えばヒドロキシプロピルメチルセルロース,エチルセルロース,ヒドロキシメチルセルロース,ヒドロキシプロピルセルロース,ポリオキシエチレングリコール,ツイーン80,ブルロニックF68,セルロースアセテートフタレート,ヒドロキシプロピルメチルセルロースフタレート,ヒドロキシメチルセルロースアセテートサクシネート,オイドラギット(ローム社製,ドイツ,メタアクリル酸・アクリル酸共重合)および色素(例、酸化チタン,ベンガラなど)などが用いられる。
【0044】
経鼻投与製剤は、固状、半固状または液状のいずれであってもよい。固状の経鼻投与製剤は、例えば上記したマイクロカプセルそのままであってもよいが、通常該マイクロカプセルに賦形剤(例、グルコース、マンニトール、デンプン、微結晶セルロースなど)、増粘剤(例、天然ガム類、セルロース誘導体、アクリル酸重合体など)などを添加、混合することにより製造できる。例えば液状の経鼻投与製剤は、上記した注射剤の場合と同様にして製造することができる。また、これらの経鼻投与製剤は、いずれも、pH調節剤(例、炭酸、リン酸、クエン酸、塩酸、水酸化ナトリウムなど)、防腐剤(例、パラオキシ安息香酸エステル類、クロロブタノール、塩化ベンザルコニウムなど)などを含んでいてもよい。
【0045】
坐剤は、油性または水性であってよく、また、固状、半固状あるいは液状のいずれであってもよい。坐剤は、通常油性基剤、水性基剤または水性ゲル基剤を用いて製造される。油性基剤としては、例えば高級脂肪酸のグリセリド〔例、カカオ脂、ウイテプゾル類(ダイナマイトノーベル社、ドイツ)など〕、中級脂肪酸〔例、ミグリオール類(ダイナマイトノーベル社、ドイツ)など〕、あるいは植物油(例、ゴマ油、大豆油、綿実油など)などが挙げられる。水性基剤としては、例えばポリエチレングリコール類、プロピレングリコールなどが挙げられる。水性ゲル基剤としては、例えば天然ガム類、セルロース誘導体、ビニール重合体、アクリル酸重合体などが挙げられる。
【0046】
本発明の徐放性製剤は、好ましくは注射剤である。本発明の徐放性製剤が注射剤である場合、該注射剤におけるマイクロカプセルなどの微粒子の粒子径は、その分散性、通針性を満足させる範囲であればよく、例えば平均径として約1から約300 μm、好ましくは約5から約100 μmである。
【0047】
本発明の徐放性製剤は、低毒性であり、哺乳動物(例、マウス、ラット、イヌ、ネコ、ヒツジ、ブタ、ウマ、ウシ、サル、ヒト等)に対し、安全に投与される。
本発明の徐放性製剤の投与量は、生理活性物質の種類と含量、生理活性物質の徐放期間、投与対象、あるいは投与目的などにより異なるが、生理活性物質の有効量であればよい。
本発明の徐放性製剤をヒトに対して用いる場合、その投与量は、例えば成人(体重50 kg)1人に1回あたり、約1mgないし約10 g、好ましくは約10 mgないし約2gの範囲から適宜選択することができる。なお、徐放性製剤が注射剤である場合の懸濁液の容量は、約0.1ないし約5 ml、好ましくは約0.5ないし約3 ml の範囲から適宜選択することができる。
特に、生理活性物質がリュープロレリンまたは酢酸リュープロレリンである場合、本発明の徐放性製剤は、ホルモン依存性の疾患(例、前立腺癌、前立腺肥大症、乳癌、子宮内膜症、子宮筋腫、中枢性思春期早発症など)および避妊などに有効である。該徐放性製剤の成人(体重50 kg)1人、1カ月あたりの投与量は、生理活性物質として、例えば約1.88〜約7.5 mgである。例えば6カ月間の徐放性製剤では、リュープロレリンまたは酢酸リュープロレリンの1回投与量は約11.3〜約45 mg、徐放性製剤の1回投与量は、約75〜約800 mgである。
一方、本発明の徐放性製剤を、家畜(例、イヌ、ネコ、ヒツジ、ブタ、ウマ、ウシ、サル等)に対し、避妊や食肉の柔軟化を目的として投与する場合、その投与量は、投与対象動物のクリアランスを測定することにより設定される。例えば投与対象動物がイヌである場合、徐放性製剤の1カ月あたりの投与量は、生理活性物質として、例えば約0.03〜約1.5 mg/kgである。例えば6カ月間の徐放性製剤では、生理活性物質の1回投与量は、約0.18〜約9 mg/kg、徐放性製剤の1回投与量は、約1.2〜約200 mg/kgである。
【0048】
【発明の実施の形態】
以下に、参考例、実施例、比較例および実験例を挙げて本発明をさらに具体的に説明するが、本発明はその要旨を超えない限りこれらに限定されるものではない。
また、以下の%(パーセント)は、特記しないかぎり、重量パーセントを示す。
【0049】
【実施例】
参考例1
開環重合法によって合成された、重量平均分子量79,900のDL-ポリ乳酸(RESORMER、R206、Lot No. 211967、ベーリンガーインゲルハイム社製、ドイツ)(以下、ポリマーFと略記)10 g を、DL-乳酸を蒸留水で1/50あるいは1/100(w/w)倍に希釈した溶液(それぞれ、pH 2.09、pH 2.27)400 ml に60℃で浸漬し、加水分解を行った。
ついで、得られる混合液から加水分解されたポリ乳酸を取り出し、それぞれ500 ml のジクロロメタンに溶解した後、それぞれ1,000 ml の蒸留水で30分間づつ3回洗浄し、水可溶性のオリゴマーを除去した。有機溶媒相をガラスシャーレに取り、ジクロロメタンを蒸発させ、40℃で減圧下1日乾燥させた。有機溶媒相が完全に固化する前に、真空度を調整して乳酸ポリマーを発泡させ、乳酸ポリマーの体積を大きくして、ジクロロメタンの蒸発を促進した。得られる発泡体を粉砕して、表1に示すポリマーを得た。
【表1】
【0050】
参考例2
参考例1と同様にして、ポリマーFの加水分解を行い、表2に示すポリマーを得た。
【表2】
【0051】
実施例1
参考例1で製造した各種ポリマーを用い、水中乾燥法により、表3に示すマイクロスフェアを製造した。
すなわち、1 mlの蒸留水に酢酸リュープロレリン550 mgを溶解する。得られる溶液に、参考例1で製造したポリマー 4 gをジクロロメタンに溶解した溶液を加え、小型ホモジナイザー(ポリトロン、キネマチカ社製、スイス)で約1分間攪拌乳化し、W/Oエマルションを得た。該W/Oエマルションを13℃に冷却した後、予め同じ温度に冷却した0.25%ポリビニールアルコール(PVA)水溶液 1,000 mlに加え、ホモミキサー(特殊機化、日本)(回転数:約7,000 rpm)を用いて乳化し、W/O/Wエマルションを得た。このW/O/Wエマルションを軽く攪拌しながら約3時間ほど脱溶媒した。得られるマイクロスフェアは、74 μm のフルイを通して荒い粒子を除去した後、遠心分離によって分取した。得られる残渣を蒸留水で3回洗浄し、遊離の薬物とPVAを除去した後、少量の水で再分散し凍結乾燥した。
【表3】
【0052】
比較例1
参考例2で製造したポリマーDおよびE、重量平均分子量22,200のDL-ポリ乳酸(RESOMER、R203、Lot No. 15004、ベーリンガーインゲルハイム社製、ドイツ)(以下、ポリマーGと略記)、重量平均分子量47,200のDL-ポリ乳酸(PL-50000、多木化学社製、日本)(以下、ポリマーHと略記)およびポリマーHを水洗して得られるポリマー(以下、ポリマーH’と略記)を用い、実施例1と同様にして、表4に示すマイクロスフェアを製造した。
【表4】
【0053】
実施例2
10 mlの蒸留水に酢酸リュープロレリン6 gを溶解する。得られる溶液に、参考例1で製造したポリマーB 44 gをジクロロメタンに溶解した後ろ過して得られる溶液190 g を加え、オートミニミキサー(回転数:6,000 rpm)で8分間攪拌乳化し、W/Oエマルションを得る。該W/Oエマルションを、約13℃に冷却した後、予め同じ温度に冷却した0.1%PVA水溶液 12 Lに加え、ホモミックラインフロー(特殊機化、日本)(回転数:約7,000 rpm)を用いて乳化し、W/O/Wエマルションを得る。このW/O/W型エマルションを軽く攪拌しながら約3時間ほど脱溶媒する。得られるマイクロスフェアは、実施例1と同様にして分取,洗浄した後、少量の水で再分散する。得られる分散液に、D-マンニトール6.4 g を溶解し、篩過後、凍結乾燥する。乾燥時の棚温度は徐々に上昇させ、最終53℃で48時間乾燥させる。得られる乾燥品を篩過粉砕してマイクロスフェア末を得る。この操作で約15%マンニトール含有のマイクロスフェア末約48 gが得られる。
【0054】
実施例3
ペプチドA1の酢酸塩4 gを6 mlの蒸留水に溶解する。得られる溶液に、参考例1で製造したポリマーB 30 gをジクロロメタンに溶解した後ろ過して得られる溶液110 g を加え、オートミニミキサー(回転数:6,000 rpm)で5分間攪拌乳化し、W/Oエマルションを得る。該W/Oエマルションを、約13℃に冷却した後、予め同じ温度に冷却した0.1%PVA水溶液 7 Lに加える。ついで、D-マンニトール量を4.3 g とする以外は実施例2と同様にしてマイクロスフェア末を得る。この操作で約15%マンニトール含有のマイクロスフェア末約33 gが得られる。
【0055】
実施例4
ソマトスタチン7.5 gを13 mlの蒸留水に溶解する。得られる溶液に、参考例1で製造したポリマーA 100 gをジクロロメタン250 mlに溶解した後ろ過して得られる溶液を加え、オートミニミキサー(回転数:6,000 rpm)で5分間攪拌乳化し、W/Oエマルションを得る。該W/Oエマルションを、約14℃に冷却した後、予め同じ温度に冷却した0.1%PVA水溶液25Lに加える。ついで、D-マンニトール量を13.7 g とし、乾燥条件を最終54℃、24時間とする以外は実施例2と同様にしてマイクロスフェア末を得る。この操作で約15%マンニトール含有のマイクロスフェア末約100 gが得られる。
【0056】
実施例5
h-GH(ヒト成長ホルモン)2 gおよびアルギニン2 gを5 mlの蒸留水に溶解する。得られる溶液に、参考例1で製造したポリマーB 30 gをジクロロメタン 96 gに溶解した後ろ過して得られる溶液を加え、オートミニミキサー(回転数:6,000 rpm)で5分間攪拌乳化し、W/Oエマルションを得る。該W/Oエマルションを、約13℃に冷却した後、予め同じ温度に冷却した0.1%PVA水溶液3 Lに加える。ついで、D-マンニトール量を4 g とし、乾燥条件を最終52℃、24時間とする以外は実施例2と同様にしてマイクロスフェア末を得る。この操作で約15%マンニトール含有のマイクロスフェア末約30 gが得られる。
【0057】
実施例6
実施例1で製造したマイクロスフェア(薬物として2.97 mg)を0.5mlの分散媒(1%カルボキシメチルセルロースナトリウム、0.5%ツイーン80を含む水溶液)に分散して注射剤を製造した。
【0058】
比較例2
比較例1で製造したマイクロスフェア(薬物として2.97 mg)を0.5mlの分散媒(1%カルボキシメチルセルロースナトリウム、0.5%ツイーン80を含む水溶液)に分散して注射剤を製造した。
【0059】
実験例1
参考例1で製造したポリマーおよび市販のポリ乳酸(開環重合法により製造され、加水分解処理を行っていないポリ乳酸)の水溶性オリゴマー(遊離酸)含量を測定した。市販のポリ乳酸としては、参考例1で用いたポリマーF、比較例1で用いたポリマーGおよびHを用いた。
遊離酸含量の測定は、各ポリマー約150 mgを精秤し、5 mlのジクロロメタンに溶解した後、10 mlの蒸留水で10分間振とう抽出し、3,000 rpmで8分間遠心分離した後の水相の2.5 mlを採り、フェノールレッドを適定試薬として1 mM水酸化ナトリウム水溶液で適定することにより行った。結果を表5に示す。
なお、ポリマーの遊離酸含量は、薬物の初期放出およびポリマー安定性に影響する重要な因子であり、遊離酸による水性チャンネル(aqueous channel)を経た初期バースト、すなわち“トンネル効果”は遊離酸が0.1%以上で顕著であることが知られている(ファーマシューティカル・リサーチ(Pharmaceutical Research), 11, (8) 1143-1147 (1994))。
【0060】
【表5】
表5から明らかなように、参考例1で得られたポリマーの遊離酸含量は、市販のポリ乳酸の遊離酸含量よりも低い値を示した。
【0061】
実験例2
ポリマーA〜HおよびH’のガラス転移温度(Tg)を測定した。結果を表6に示す。
【表6】
【0062】
実験例3
実施例1および比較例1で製造したマイクロスフェアのガラス転移温度(Tg)、薬物含量およびトラップ率を測定した。結果を表7に示す。
【表7】
【0063】
表7から明らかなように、開環重合により製造したポリ乳酸を加水分解しないポリマー(ポリマーGおよびH)およびポリマーHを水洗して得られるポリマー(ポリマーH')を用いて製造したマイクロスフェア(マイクロスフェアG、HおよびH')では、薬物含量およびトラップ率が低かった。また、前記表3および4から明らかなように、これらのマイクロスフェアの収率は低かった。
さらに、開環重合により製造したポリ乳酸を加水分解して得られるポリマーであっても、分子量が60,000より大きいポリマー(ポリマーDおよびE)を用いて製造したマイクロスフェア(マイクロスフェアDおよびE)では、トラップ率がやや低かった。また、前記表3および4から明らかなように、これらのマイクロスフェアの収率は低かった。
加水分解処理を行わないポリマーには環状のポリマーが多く存在し、末端にカルボン酸基を有するポリ乳酸が少ない。よって、このようなポリマーを用いて製造したマイクロスフェアにおいては、ポリマーと薬物との相互作用が少なく、ポリマーによる薬物粒子の包み込み効果が小さいので、トラップ率が低下すると考えられる。
また、ポリマーの分子量が大きくなると、ポリマーの疎水性基に対する親水性カルボン酸基の割合が少なくなる。よって、このようなポリマーを用いて製造したマイクロスフェアにおいても、ポリマーによる薬物粒子の包み込み効果が小さくなり、トラップ率が低下すると考えられる。
したがって、マイクロスフェア中に良好に薬物を包含させるためには、ポリマー鎖の末端に、疎水アルキル基に対する割合が適度のカルボン酸基の存在が必要であると考えられる。
【0064】
実験例4
実施例6および比較例2で製造した注射剤をラットに皮下投与〔投与量:薬物として2.97 mg/ラット(30μg/kg/日)、n=5〕した後、経時的に皮下に残存する薬物(酢酸リュープロレリン)を定量し、薬物放出性を評価した。結果を表8に示す。
【表8】
表8から明らかなように、本発明のマイクロスフェア(マイクロスフェアAおよびB)は、初期バーストが少なく、その後約6カ月の長期にわたり薬物をほぼ連続的にゼロ次放出した。一方、分子量が大きく生体内分解性の遅いポリ乳酸を用いているにもかかわらず、マイクロスフェアDおよびEは、初期バーストが大きいだけでなく、17週でほとんどの薬物を放出し、その後の放出がほとんど見られなかった。
【0065】
【発明の効果】
本発明のポリマーを用いることにより、高収率で、薬物取り込み率および薬物含量が高く、初期バーストの小さい徐放性製剤(特にマイクロスフェア)を製造することができる。さらに、本発明のポリマーは、有害な触媒および有機溶媒等を実質的に含まないので、安全性が高い。
本発明の徐放性製剤は、分散性が良好で操作性に優れる。また、該徐放性製剤は、保存安定性に優れ、長期保存が可能である。さらに、本発明の徐放性製剤は、約5カ月以上の長期にわたり、生理活性物質をほぼ連続的にゼロ次放出することができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a sustained-release preparation that releases a physiologically active substance over about 5 months or more.
[0002]
[Prior art]
As for microsphere type sustained-release preparations of drugs using biodegradable polymers, for example, JP-A-57-118512 (EP-A 52510), JP-A-57-150609 (EP-A 58481), JP-A-60-100516 (EP-A 145240), JP-A-62-201816 (EP-A 190833), JP-A-4-321622 (EP-A 442671), JP-A-7-97334 (EP-A 601799). In particular, JP-A-60-100516 (EP-A 145240) and JP-A-62-201816 (EP-A 190833) describe a water-soluble drug having a high trap rate and good dispersibility by an underwater drying method. A method for producing sustained release microcapsules is disclosed. JP-A-4-321622 (EP-A 442671) contains a copolymer or homopolymer having a lactic acid / glycolic acid composition ratio of 80/20 to 100/0 and a weight average molecular weight of 7,000 to 30,000 for 2 months. Over the above, long-term sustained release microcapsules that release the polypeptide in zero order have been disclosed.
[0003]
[Problems to be solved by the invention]
However, a sustained-release preparation containing a lactic acid polymer having a weight average molecular weight of about 25,000 to about 60,000 and a physiologically active substance and releasing the physiologically active substance for about 5 months or more is not known.
[0004]
[Means for Solving the Problems]
The present invention
(1) A sustained-release preparation containing a lactic acid polymer having a weight average molecular weight of about 25,000 to about 60,000 and a bioactive substance, and releasing the bioactive substance over about 5 months,
(2) The sustained release preparation according to the above (1), wherein the lactic acid polymer is obtained by hydrolyzing polylactic acid produced by ring-opening polymerization,
(3) The sustained-release preparation according to the above (1), wherein the lactic acid polymer does not substantially contain a catalyst,
(4) The sustained release preparation according to the above (1), wherein the lactic acid polymer has a weight average molecular weight of about 30,000 to about 50,000,
(5) The sustained release preparation according to the above (1), wherein the lactic acid polymer has a dispersity of about 1.2 to about 4.0,
(6) The sustained release preparation according to the above (1), which is for injection,
(7) The sustained release preparation according to the above (1), further comprising an excipient,
(8) The sustained release preparation according to the above (7), wherein the excipient is a saccharide.
(9) The sustained release preparation according to the above (1), wherein the physiologically active substance is a physiologically active peptide,
(10) The sustained-release preparation according to the above (9), wherein the physiologically active peptide is an LHRH agonist or LHRH antagonist,
(11) LHRH agonist is formula
(Pyr) Glu-R1-Trp-Ser-R2-RThree-RFour-Arg-Pro-RFive (I)
[Where R1Is His, Tyr, Trp or p-NH2-Phe; R2Is Tyr or Phe; RThreeIs Gly or an optionally substituted D-type amino acid residue; RFourIs Leu, Ile or Nle; RFiveIs Gly-NH-R6(R6Is an alkyl group with or without a hydrogen atom or hydroxyl group) or NH-R7(R7Represents a hydrogen atom, an alkyl group with or without an amino group or a hydroxyl group, or a ureido)] or a salt thereof, a sustained release preparation according to the above (10),
(12) The sustained-release preparation according to the above (11), wherein the peptide represented by the formula (I) or a salt thereof is leuprorelin or leuprorelin acetate,
(13) The sustained release preparation according to the above (1), wherein the content of the physiologically active substance in the sustained release preparation is about 0.01 to about 50% (W / W),
(14) The sustained-release preparation according to the above (1), wherein the ratio of the physiologically active substance to the lactic acid polymer is about 0.01 to about 50% (w / w),
(15) The sustained release according to the above (1), wherein the physiologically active substance is leuprorelin acetate, the lactic acid polymer has a weight average molecular weight of about 28,400 to about 47,800, and releases leuprorelin acetate for about 6 months or more. Sex preparations, and
(16) Microencapsulating a w / o emulsion having a solution containing a physiologically active substance as an inner aqueous phase and a solution containing a lactic acid polymer having a weight average molecular weight of about 25,000 to about 60,000 as an oil phase, The present invention relates to a method for producing a sustained-release preparation that releases a physiologically active substance over 5 months.
[0005]
In the present specification, with respect to the weight average molecular weight and the degree of dispersion, the former is a gel permeation using nine kinds of polystyrenes having a weight average molecular weight of 120,000, 52,000, 22,000, 9,200, 5,050, 2,950, 1,050, 580, 162 as reference materials. It is a value in terms of polystyrene measured by chromatography (GPC), and the latter is a value calculated from this value. The measurement used GPC column KF804L (Showa Denko, Japan) × 2, RI monitor L-3300 (Hitachi, Japan), and chloroform as the mobile phase.
In addition, abbreviations such as amino acids and protecting groups, and abbreviations used in this specification are abbreviations by IUPAC-IUB Commission on Biochemical Nomenclature or conventional abbreviations in the field. If there is an optical isomer related to an amino acid, the L form is indicated unless otherwise specified.
Furthermore, the abbreviations used in this specification have the following meanings.
NAcD2Nal: N-acetyl-D-3- (2-naphthyl) alanyl
D4ClPhe: D-3- (4-chlorophenyl) alanyl
D3Pal: D-3- (3-pyridyl) alanyl
NMeTyr: N-methyltyrosyl
DLys (Nic): D- (epsilon-N-nicotinoyl) lysyl
Lys (Nisp): (epsilon-N-isopropyl) lysyl
DhArg (Et2): D- (N, N'-diethyl) homoarginyl
[0006]
The lactic acid polymer used in the present invention is a biodegradable polymer that decomposes in vivo for about 5 months or more and has a free carboxyl group at the terminal. The polymer is a homopolymer of lactic acid.
The weight average molecular weight of the lactic acid polymer of the present invention is about 25,000 to about 60,000, preferably about 27,000 to about 55,000, more preferably about 28,000 to about 50,000. Sustained release formulations can be produced with few bursts and showing a continuous zero order release of the drug over about 5 months or more. The dispersity (weight average molecular weight / number average molecular weight) of the lactic acid polymer used in the present invention is preferably about 1.2 to about 4.0, more preferably about 1.5 to about 3.5.
The lactic acid polymer of the present invention may be any of L-, D- and DL-forms, and the DL-form is particularly preferred. In the DL-form, the D-form / L-form (mol%) is preferably about 75/25 to about 20/80, more preferably about 60/40 to about 25/75, particularly preferably about 55 / 45 to about 25/75.
[0007]
The lactic acid polymer used in the present invention is preferably produced by hydrolyzing a raw polylactic acid produced by a ring-opening polymerization reaction of a cyclic dimer of lactic acid.
Here, the raw polylactic acid produced by the ring-opening polymerization reaction is a method in which a catalyst is added and heated under reduced pressure to dehydrate and condense lactic acid (JP 56-45920, EP-A 26599) or lactic acid in the absence of a catalyst. Is a polymer in a high molecular region which cannot be obtained by a method for synthesizing a polymer containing substantially no catalyst (JP-A 61-28521, EP-A 172636). The ring-opening polymerization reaction (sometimes abbreviated as ring-opening polymerization) is a method in which a cyclic dimer of lactic acid is used and a catalyst is added under heating [eg, JHR Woodland The Journal of Medicinal Chemistry (J. Med. Chem.), 16, 897 (1973)].
The weight average molecular weight of the polylactic acid produced by ring-opening polymerization is not particularly limited as long as it is larger than the weight average molecular weight (about 25,000 to about 60,000) of the lactic acid polymer obtained by hydrolysis, but for example, about 50,000 to about 200,000, preferably About 60,000 to about 100,000.
As the polylactic acid produced by the above ring-opening polymerization, commercially available products can be used.
[0008]
The hydrolysis of polylactic acid produced by ring-opening polymerization, which is performed to obtain the lactic acid polymer used in the present invention, is performed in the presence of an acid or a base according to a known method. Furthermore, the hydrolysis is carried out in the presence of water.
Examples of the acid include inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, and phosphoric acid, and organic acids such as lactic acid, acetic acid, tartaric acid, citric acid, and succinic acid. Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and alkali metal carbonates such as sodium carbonate and potassium carbonate. When the hydrolysis is performed in the presence of a base, the release of the physiologically active substance from the sustained-release preparation is affected by the remaining amount of the base. Therefore, the hydrolysis is preferably performed in the presence of an acid.
Hydrolysis is usually performed in a solvent that does not adversely affect the reaction. Examples of such a solvent include alcohols such as methanol, ethanol and propanol, ethers such as tetrahydrofuran, dioxane, diethyl ether and diisopropyl ether, water, and a mixed solvent thereof. In addition, an excess amount of the acid or base described above may be used as a solvent.
The temperature during the hydrolysis is, for example, about 0 to about 100 ° C, preferably about 10 to about 100 ° C.
The time required for hydrolysis varies depending on the weight average molecular weight of polylactic acid produced by ring-opening polymerization, the type of acid or base, the type of solvent, the temperature, etc., so a part of polylactic acid and lactic acid polymer are collected during hydrolysis Then, it may be determined appropriately by measuring the weight average molecular weight of the collected polylactic acid and lactic acid polymer. The time required for hydrolysis is not particularly limited, and is, for example, about 1 hour to about 10 days, preferably about 10 hours to about 5 days.
Polylactic acid produced by ring-opening polymerization can produce only sustained-release preparations with a large initial burst, but hydrolyzed polylactic acid, that is, the lactic acid polymer used in the present invention, produces sustained-release preparations with a small initial burst. can do.
[0009]
It is preferable that the hydrolyzed polylactic acid is further subjected to a purification step. The purification step is performed by dissolving hydrolyzed polylactic acid in an organic solvent, injecting the resulting solution into water or a mixed solution of water and a water-soluble organic solvent, and separating the precipitated lactic acid polymer.
Examples of organic solvents include halogenated hydrocarbons (eg, dichloromethane, chloroform, chloroethane, dichloroethane, trichloroethane, carbon tetrachloride), ketones (eg, acetone), ethers (eg, tetrahydrofuran, ethyl ether, isopropyl). Ether, etc.), esters (eg, ethyl acetate, butyl acetate, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.) and the like. The amount of the organic solvent used is, for example, about 3 to about 20 times (w / v) with respect to the hydrolyzed polylactic acid.
Examples of the water-soluble organic solvent include acetone, methanol, ethanol, tetrahydrofuran, acetonitrile, and the like. The amount of water or a mixture of water and a water-soluble organic solvent is not particularly limited, but is usually a large excess with respect to hydrolyzed polylactic acid.
The temperature in the purification step is usually about 0 to about 90 ° C, preferably about 20 to about 70 ° C.
By the purification step described above, water-soluble low molecular weight compounds (for example, those having a weight average molecular weight of about 1,000 or less) can be removed. By using a lactic acid polymer obtained through such a purification process, it is possible to increase the uptake rate (trap rate) of a physiologically active substance when producing a sustained-release preparation, and to reduce the initial burst. Sex preparations can be produced.
Further, by subjecting polylactic acid produced by ring-opening polymerization to hydrolysis and purification steps, harmful catalysts used in ring-opening polymerization (eg, zinc compounds such as zinc oxide and stannous octoate) It is possible to produce a lactic acid polymer substantially free of a tin compound).
[0010]
The physiologically active substance suitably used in the present invention is not particularly limited, but a physiologically active peptide, antibiotic, antitumor agent, antipyretic, analgesic, anti-inflammatory agent, antitussive expectorant, sedative, muscle relaxant, antiepileptic Agent, anti-ulcer agent, antidepressant agent, antiallergic agent, cardiotonic agent, arrhythmia agent, vasodilator, antihypertensive diuretic agent, antidiabetic agent, antilipidemic agent, anticoagulant agent, hemostatic agent, antituberculosis agent, Hormonal agents, narcotic antagonists, bone resorption inhibitors, bone formation promoters, angiogenesis inhibitors and the like can be mentioned.
The physiologically active peptide is preferably composed of two or more amino acids and having a molecular weight of about 200 to about 80,000. The bioactive peptide is preferably an LHRH (Luteinizing Hormone Releasing Hormone) agonist or LHRH antagonist.
Examples of LHRH agonists include:
Formula: (Pyr) Glu-R1-Trp-Ser-R2-RThree-RFour-Arg-Pro-RFive (I)
[Where R1Is His, Tyr, Trp or p-NH2-Phe; R2Is Tyr or Phe; RThreeIs Gly or an optionally substituted D-type amino acid residue; RFourIs Leu, Ile or Nle; RFiveIs Gly-NH-R6(R6Is an alkyl group with or without a hydrogen atom or hydroxyl group) or NH-R7(R7Is a hydrogen atom, an alkyl group with or without an amino or hydroxyl group, or a ureido (-NH-CO-NH2))]] Or a salt thereof.
[0011]
In the above formula (I), RThreeExamples of the D-type amino acid residue in A include α-D-amino acids having up to 9 carbon atoms (eg, D-Leu, Ile, Nle, Val, Nval, Abu, Phe, Phg, Ser, Thr, Met, Ala , Trp, α-Aibu). RThreeExamples of the substituent in tert-butyl, tert-butoxy, tert-butoxycarbonyl, methyl, dimethyl, trimethyl, 2-naphthyl, indolyl-3-yl, 2-methylindolyl, benzyl-imidazol-2-yl, etc. Is mentioned.
In formula (I), R6Or R7As the alkyl group in, for example, C1-4Alkyl groups are preferred, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
Examples of the salt of the peptide represented by the formula (I) [hereinafter sometimes abbreviated as peptide (I)] include, for example, acid salts (eg, carbonate, bicarbonate, acetate, trifluoroacetate). , Propionate, succinate, etc.) and metal complex compounds (eg, copper complexes, zinc complexes, etc.).
Peptide (I) or a salt thereof is disclosed in, for example, U.S. Pat. Manufactured by the method described in Proceedings of the National Academy of Sciences of the United States of America, Vol. 78, pp. 6509-6512 (1981), or the like be able to.
[0012]
Peptide (I) is preferably any of the following formulas (a) to (j).
(A) Leuprorelin [Leuprorelin, R in formula (I)1= His, R2= Tyr, RThree= D-Leu, RFour= Leu, RFive= NHCH2-CHThree(B) Gonadrelin
[Chemical 1]
[German Patent No. 2213737]; (c) Buserelin
[Chemical formula 2]
[US Pat. No. 4,024,248, German Patent 2,243,352, Japanese Patent Laid-Open No. 51-41359]; (d) Triptorelin
[Chemical 3]
[US Pat. No. 4,010,125, JP-A-52-31073]; (e) Goserelin
[Formula 4]
[U.S. Pat. No. 4,100,274, JP-A-52-136172]; (f) Nafarelin
[Chemical formula 5]
[U.S. Pat. No. 4,423,571, JP-A-55-164663, JP-A-63-264498, JP-A-64-25794]; (g) Histrelin
[Chemical 6]
; (H) Deslorelin
[Chemical 7]
[US Pat. No. 4,569,967, US Pat. No. 4,218,439]; (i) Meterelin
[Chemical 8]
[WO9118016]; (j) Recirelin
[Chemical 9]
[Belgium Patent No. 897455, JP-A-59-59654] and the like.
In the above formulas (c) to (j), R in formula (I)ThreeThe amino acid corresponding to is D-form.
Peptide (I) or a salt thereof is particularly preferably leuprorelin or leuprorelin acetate. Here, leuprorelin acetate is leuprorelin acetate.
[0013]
Examples of LHRH antagonists include those disclosed in US Pat. Nos. 4,086,219, 4,124,577, 4,253,997, and 4,317,815, or
Embedded image
[Wherein, X represents hydrogen or tetrahydrofurylcarboxamide, Q represents hydrogen or methyl, A represents nicotinoyl or N, N′-diethylamidino, and B represents isopropyl or N, N′-diethylamidino] (Hereinafter sometimes abbreviated as peptide (II)) or a salt thereof.
In the formula (II), X is preferably tetrahydrofurylcarboxamide, more preferably (2S) -tetrahydrofurylcarboxamide. A is preferably nicotinoyl. B is preferably isopropyl.
In addition, when peptide (II) has one or more asymmetric carbon atoms, two or more optical isomers exist. Peptide (II) may be used as such an optical isomer or as a mixture of these optical isomers.
[0014]
As the peptide (II) salt, a pharmacologically acceptable salt is preferably used. Examples of such salts include salts with inorganic acids (eg, hydrochloric acid, sulfuric acid, nitric acid, etc.), organic acids (eg, carbonic acid, bicarbonate, succinic acid, acetic acid, propionic acid, trifluoroacetic acid, etc.). . The salt of peptide (II) is more preferably a salt with an organic acid (eg, carbonic acid, bicarbonate, succinic acid, acetic acid, propionic acid, trifluoroacetic acid, etc.). The salt of peptide (II) is particularly preferably a salt with acetic acid. These salts may be mono- or tri-salts.
[0015]
Peptide (II) or a salt thereof is preferably represented by the following formulas (1) to (4).
Embedded image
[Wherein m represents a real number of 1 to 3]
(3) NAcD2Nal-D4ClPhe-D3Pal-Ser-Tyr-DhArg (Et2) -Leu-hArg (Et2) -Pro-DAlaNH2
(4) NAcD2Nal-D4ClPhe-D3Pal-Ser-Tyr-DhArg (Et2) -Leu-hArg (Et2) -Pro-DAlaNH2・ N (CHThreeCOOH)
[Wherein n represents a real number of 1 to 3]
The above formulas (2) and (4) represent salts or solvates.
Peptide (II) or a salt thereof is more preferably the above (1) or (2), and it is particularly preferable that these are S-isomers. Hereinafter, the S-isomer of (1) is abbreviated as peptide A1.
[0016]
Peptide (II) or a salt thereof can be obtained by a method known per se, for example, Japanese Patent Laid-Open No. 3-101695 (EP-A 413209), Journal of Medicinal Chemistry, Vol. 35, page 3942, (1992). Etc., or a similar method.
[0017]
Examples of physiologically active peptides preferably used in the present invention include insulin, somatostatin, somatostatin derivatives (see Sandstatin, US Pat. Nos. 4,087,390, 4,093,574, 4,100,117, and 4,253,998), growth Hormone, prolactin, adrenocorticotropic hormone (ACTH), ACTH derivatives (eg, shrimp tide), melanocyte stimulating hormone (MSH), thyroid hormone releasing hormone [(Pyr) Glu-His-ProNH2 And the salts thereof and derivatives thereof (see JP-A-50-121273, JP-A-52-116465), thyroid stimulating hormone (TSH), corpus luteum Forming hormone (LH), follicle stimulating hormone (FSH), vasopressin, vasopressin derivatives {Desmopressin [Japanese Journal of Endocrine Society, Vol. 54, No. 5, 676-691 (1978)]}, oxytocin, calcitonin, parathyroid hormone (PTH), glucagon, gastrin, secretin, pancreosimine, cholecystokinin, angiotensin, human placental lactogen, human chorionic gonadotropin (HCG), enkephalin, enkephalin derivative [US Pat. No. 4,277,394, European Patent Application Publication No. 31567 No. Publication], Endorphin, Kyotorphin, Interferon (Eg, α type, β type, γ type, etc.), interleukins (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc.), tuftsin, thymopoietin, Thymosin, thymostimulin, thymic factor (THF), blood thymic factor (FTS) and its derivatives (see US Pat. No. 4,229,438), and other thymic factors [A medical history, Vol. 125, No. 10, 835] -843 (1983)], tumor necrosis factor (TNF), colony-inducing factor (CSF, GCSF, GMCSF, MCSF, etc.), motilin, dynorphin, bombesin, neurotensin, cerulein, bradykinin, urokinase, asparaginase, kallikrein , Substance P, insulin-like growth factor (IGF-I, IGF-II), nerve growth factor (NGF), cell growth factor (EGF, TGF-α, TG) -Β, PDGF, acidic FGF, basic FGF, etc.), bone morphogenetic factor (BMP), neurotrophic factor (NT-3, NT-4, CNTF, GDNF, BDNF, etc.), factor VIII of blood coagulation factor, Factor IX, lysozyme chloride, polymyxin B, colistin, gramicidin, bacitracin and erythropoietin (EPO), thrombopoietin (TPO), peptides having an endothelin antagonistic activity (European Patent Publication Nos. 436189, 457195, 496452, JP-A-3-94692 and JP-A-3-130299).
[0018]
Antibiotics include, for example, gentamicin, dibekacin, cannendomycin, libidomycin, tobramycin, amikacin, fradiomycin, sisomycin, tetracycline hydrochloride, oxytetracycline hydrochloride, loritetracycline, doxycycline hydrochloride, ampicillin, piperacillin, ticarcillin, cephalothin, cephalolidine, Examples include cefotiam, cefsulodin, cefmenoxime, cefmetazole, cefazoline, cefotaxime, cefoperazone, ceftioxime, moxalactam, thienamycin, sulfazecin, and azuleonam.
Antitumor agents include, for example, bleomycin, methotrexate, actinomycin D, mitomycin C, vinblastine sulfate, vincristine sulfate, daunorubicin, adriamycin, neocalcinostatin, cytosine arabinoside, fluorouracil, tetrahydrofuryl-5-fluorouracil, krestin, picibanil , Lentinan, levamisole, bestatin, azimexone, glycyrrhizin, poly I: C, poly A: U, poly ICLC, and the like.
[0019]
Examples of antipyretic, analgesic and anti-inflammatory agents include salicylic acid, sulpyrine, flufenamic acid, diclofenac, indomethacin, morphine, pethidine hydrochloride, levorphanol tartrate, oxymorphone, and the like.
Examples of antitussive expectorants include ephedrine hydrochloride, methylephedrine hydrochloride, noscapine hydrochloride, codeine phosphate, dihydrocodeine phosphate, aloclamide hydrochloride, clofedanol hydrochloride, picoperidamine hydrochloride, cloperastine, protochelol hydrochloride, isoproterenol hydrochloride, salbutamol sulfate And terbutaline sulfate.
Examples of the sedative include chlorpromazine, prochlorperazine, trifluoroperazine, atropine sulfate, methyl scopolamine bromide and the like.
Examples of the muscle relaxant include pridinol methanesulfonate, tubocurarine chloride, pancuronium bromide and the like.
Examples of the antiepileptic agent include phenytoin, ethosuximide, acetazolamide sodium, chlordiazepoxide and the like.
Examples of the anti-ulcer agent include metoclopromide and histidine hydrochloride.
Examples of the antidepressant include imipramine, clomipramine, noxiptillin, phenelzine sulfate and the like.
[0020]
Examples of the antiallergic agent include diphenhydramine hydrochloride, chlorpheniramine maleate, tripelenamine hydrochloride, methodirazine hydrochloride, clemizole hydrochloride, diphenylpyraline hydrochloride, methoxyphenamine hydrochloride and the like.
Examples of the cardiotonic agent include transpyoxocamphor, theophylol, aminophylline, ethylephrine hydrochloride and the like.
Examples of the arrhythmia therapeutic agent include propranol, alprenolol, bufetrol, oxyprenolol and the like.
Examples of the vasodilator include oxyfedrine hydrochloride, diltiazem, tolazoline hydrochloride, hexobenzine, and bamethane sulfate.
Examples of the antihypertensive diuretic include hexamethonium bromide, pentolinium, mecamylamine hydrochloride, ecarazine hydrochloride, clonidine and the like.
Examples of the diabetes therapeutic agent include grimidine sodium, glipizide, phenformin hydrochloride, buformin hydrochloride, metformin and the like.
Examples of the antilipidemic agent include pravastatin sodium, simvastatin, clinofibrate, clofibrate, simfibrate, bezafibrate and the like.
[0021]
Examples of the anticoagulant include heparin sodium.
Examples of the hemostatic agent include thromboplastin, thrombin, menadione sodium bisulfite, acetomenafton, ε-aminocaproic acid, tranexamic acid, sodium carbazochrome sulfonate, and adrenochrome monoaminoguanidine methanesulfonate.
Examples of antituberculosis agents include isoniazid, ethambutol, and paraaminosalicylic acid.
Examples of the hormone agent include prednisolone, sodium prednisolone phosphate, sodium dexamethasone sulfate, betamethasone sodium phosphate, hexestrol phosphate, hexestrol acetate, and methimazole.
Examples of narcotic antagonists include levalorphan tartrate, narolphine hydrochloride, naloxone hydrochloride, and the like.
Examples of the bone resorption inhibitor include ipriflavone, alendronate, risedronate and the like.
Examples of osteogenesis promoters include (2R, 4S)-(−)-N- [4- (diethoxyphosphorylmethyl) phenyl] -1 in addition to polypeptides such as BMP, PTH, TGF-β, and IGF-1. , 2,4,5-Tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxamide, 2- (3-pyridyl) -ethane-1,1-diphosphonic acid, Raloxifene and the like can be mentioned.
Examples of the angiogenesis inhibitor include angiogenesis-inhibiting steroids [see Science, Vol. 221, page 719 (1983)], fumagillin (see European Patent Publication No. 325199), fumagillol derivatives (European Patent Publication No. 357061). No. 359036, No. 386667, No. 415294), Batachi Must, and the like.
[0022]
The physiologically active substance itself may be used as a pharmacologically acceptable salt. For example, when the physiologically active substance has a basic group such as an amino group, a salt with an inorganic acid (eg, hydrochloric acid, sulfuric acid, nitric acid, etc.) or an organic acid (eg, carbonic acid, succinic acid, etc.) is used. In addition, when the physiologically active substance has an acidic group such as a carboxy group, an inorganic base (eg, alkali metal such as sodium or potassium) or an organic base (eg, organic amines such as triethylamine, basic amino acids such as arginine) Etc.) is used.
[0023]
The physiologically active substance used in the sustained-release preparation of the present invention is preferably a physiologically active peptide, more preferably an LHRH agonist or LHRH antagonist. The physiologically active substance is particularly preferably an LHRH agonist, particularly peptide (I) or a salt thereof.
[0024]
The content of the physiologically active substance in the sustained-release preparation varies depending on the type of the physiologically active substance, the desired pharmacological effect and the duration of the effect, etc., for example, about 0.01 to about 50% (W / W), preferably about 0.1 Or about 30% (W / W).
[0025]
The sustained-release preparation of the present invention only needs to contain fine particles (that is, microspheres) containing a physiologically active substance and a lactic acid polymer. Specific examples of the microparticles (ie, microspheres) include, for example, microcapsules containing one bioactive substance core in one particle, and multinuclear micros containing many bioactive substance cores in one particle. Examples thereof include capsules and fine particles in which a physiologically active substance in a molecular form is dissolved or dispersed in a lactic acid polymer as a solid solution.
[0026]
As a preferable example of the sustained-release preparation of the present invention, the physiologically active substance is leuprorelin acetate, the lactic acid polymer has a weight average molecular weight of about 28,400 to about 47,800, and leuprorelin acetate for about 6 months or more. Sustained-release preparations that release
[0027]
The sustained-release preparation of the present invention is produced, for example, by microencapsulating a W / O emulsion having a solution containing a physiologically active substance as an inner aqueous phase and a solution containing a lactic acid polymer as an oil phase. The microencapsulation is performed by, for example, an underwater drying method, a phase separation method, a spray drying method, or a method analogous thereto.
A W / O emulsion having a solution containing a physiologically active substance as an inner aqueous phase and a solution containing a lactic acid polymer of the present invention as an oil phase can be produced as follows.
First, a physiologically active substance is dissolved in water so as to have a concentration of about 0.001 to about 90% (w / w), preferably about 0.01 to about 80% (w / w) to form an inner aqueous phase. The inner aqueous phase retains drugs such as gelatin, agar, sodium alginate, polyvinyl alcohol, or basic amino acids (eg, arginine, lysine, etc.) to improve the uptake rate of physiologically active substances into microcapsules. Substances may be added. The added amount of the drug-holding substance is usually about 0.01 to about 100 times by weight, more preferably about 0.05 to about 50 times by weight with respect to the physiologically active substance. These drug-retaining substances can be dissolved in water together with a physiologically active substance at an arbitrary concentration in advance, filtered using a sterilization / dust removal filter, stored freeze-dried, and dissolved and used at the time of preparation.
In the sustained-release preparation of the present invention, the uptake rate of the physiologically active substance is sufficiently satisfactory even when no drug retaining substance is used in the inner aqueous phase.
[0028]
In addition, as a pH adjuster for maintaining the stability and solubility of physiologically active substances in the inner aqueous phase, carbonic acid, acetic acid, oxalic acid, citric acid, phosphoric acid, hydrochloric acid, sodium hydroxide, arginine, lysine and those A salt of the above may be added. Further, as stabilizers for bioactive substances, albumin, gelatin, trehalose, citric acid, ethylenediaminetetraacetate sodium, dextrin, cyclodextrin (α-, β-, γ-) and derivatives thereof (eg, maltosyl β- Cyclodextrin, β-cyclodextrin sulfobutyl ether, etc.), polyol compounds such as sodium bisulfite, polyethylene glycol, polyoxyethylene sorbitan fatty acid ester [eg, Tween 80, Tween 60 (Kao, Japan)], polyoxyethylene castor oil Add surfactants such as derivatives [eg, HCO-60, HCO-70 (Nikko Chemicals, Japan)], paraoxybenzoates (eg, methylparaben, propylparaben, etc.), benzyl alcohol, chlorobutanol, thimerosal, etc. May be.
[0029]
The inner aqueous phase thus obtained and a solution (oil phase) containing a lactic acid polymer are mixed, and the resulting mixture is subjected to an emulsification step to prepare a W / O emulsion.
As the solution (oil phase) containing the lactic acid polymer, a solution obtained by dissolving the lactic acid polymer in an organic solvent is used. The organic solvent is not particularly limited as long as it has a boiling point of about 120 ° C. or less, is hydrophobic, and dissolves a lactic acid polymer. For example, halogenated hydrocarbons (eg, dichloromethane, chloroform, chloroethane, dichloroethane, trichloroethane, carbon tetrachloride). Etc.), fatty acid esters (eg, ethyl acetate, butyl acetate, etc.), ethers (eg, ethyl ether, isopropyl ether, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.) and the like. Two or more of these organic solvents may be mixed and used at an appropriate ratio. The organic solvent is preferably a halogenated hydrocarbon, particularly preferably dichloromethane.
The concentration of the lactic acid polymer in the organic solvent varies depending on the type of lactic acid polymer, the molecular weight, and the type of organic solvent, but is usually about 0.01 to about 90% (w / w), preferably about 0.1 to about 80% (w / w ).
In order to change the compatibility with the inner aqueous phase, the distribution of the organic solvent to the outer aqueous phase, volatilization, etc., a partially hydrophilic organic solvent such as ethanol, acetonitrile, acetone, tetrahydrofuran, etc. is added to the oil phase. May be. In addition, a surfactant such as sucrose fatty acid ester may be added to dissolve or stabilize the internal physiologically active substance.
The oil phase thus obtained is usually used after sterilization and dust filtration with a filter. Depending on the stability of the lactic acid polymer, a solution containing the lactic acid polymer may be stored in a sealed container at room temperature or in a cold place.
[0030]
The mixing ratio of the aqueous solution of the physiologically active substance and the organic solvent solution of the lactic acid polymer is about 0.1 to about 1000 parts by weight, preferably about 1 to about 100 parts by weight with respect to the former. In addition, the ratio of the physiologically active substance to the lactic acid polymer is about 0.01 to about 50% (w / w), preferably about 0.5 to about 0.5, depending on the type of physiologically active substance, the desired pharmacological effect and the duration of the effect. It is advisable to mix such that it is 40% (w / w), particularly preferably about 0.1 to about 30% (w / w).
[0031]
The emulsification step is performed by a known dispersion method such as an intermittent shaking method, a method using a stirrer such as a propeller stirrer or a turbine stirrer, a colloid mill method, a homogenizer method, or an ultrasonic irradiation method. In this W / O emulsion, the release of the physiologically active substance is affected by the degree of emulsification, and if the degree of emulsification is insufficient, the initial burst tends to be large, and the inner aqueous phase becomes finer than a certain level. The interaction between the physiologically active substance and the lactic acid polymer is strong, and the release control by the lactic acid polymer is preferable because long-term release control can be made more accurately depending on the biodegradability of the lactic acid polymer.
[0032]
Next, the W / O emulsion thus obtained is subjected to a microencapsulation process.
For example, when microencapsulation is performed by an underwater drying method, a W / O emulsion is further added to an aqueous phase (hereinafter abbreviated as an outer aqueous phase), and a W / O / W emulsion is produced, followed by an organic solvent in the oil phase. To prepare microcapsules.
An emulsifier may be added to the outer aqueous phase. The emulsifier may be any as long as it generally forms a stable O / W emulsion. For example, an anionic surfactant (eg, sodium oleate, sodium stearate, sodium lauryl sulfate), a nonionic interface Active agents (eg, Tween 80, Tween 60, HCO-60, HCO-70, etc.), polyvinyl alcohol, polyvinyl pyrrolidone, gelatin and the like can be mentioned. Two or more of these emulsifiers may be mixed and used at an appropriate ratio. The concentration of the emulsifier in the outer aqueous phase is, for example, about 0.01 to about 20%, preferably about 0.05 to about 10%.
The removal of the organic solvent may be performed according to a known method. As such a method, for example, a method of removing the solvent under normal pressure or gradually reducing pressure while stirring with a propeller type stirrer or a magnetic stirrer, etc., while adjusting the degree of vacuum and temperature using a rotary evaporator or the like Examples include a method for removing the solvent.
The microcapsules thus obtained are separated by centrifugation or filtration, and then washed several times with distilled water, so that free physiologically active substances, drug-retaining substances, and emulsifiers attached to the surface of the microcapsules Etc. are removed. Subsequently, the washed microcapsules are dried under reduced pressure, or redispersed in distilled water and lyophilized to further remove the organic solvent.
[0033]
When microencapsulation is performed by a phase separation method, a microcapsule is prepared by gradually adding a coacervation agent to a W / O emulsion under stirring to precipitate and solidify a lactic acid polymer.
The coacervation agent may be a polymer, mineral oil, or vegetable oil compound that is miscible with the lactic acid polymer solvent and does not dissolve the lactic acid polymer for encapsulation. For example, silicone oil, sesame oil, Examples include soybean oil, corn oil, cottonseed oil, coconut oil, linseed oil, mineral oil, n-hexane, and n-heptane. You may use these in mixture of 2 or more types. The amount of the coacervation agent to be used is, for example, about 0.01 to about 1,000 times by volume, preferably about 0.1 to about 200 times by volume with respect to the W / O emulsion.
The microcapsules thus obtained are separated by centrifugation or filtration, and then repeatedly washed with a washing liquid such as hexane or heptane to remove the coacervation agent. Then, the washing liquid is heated or reduced in pressure. Evaporate. Further, if desired, the free physiologically active substance and the organic solvent are removed in the same manner as in the above-described drying method in water.
[0034]
When microencapsulation is performed by the spray drying method, a W / O emulsion or a W / O / W emulsion produced in the same manner as the underwater drying method is used in the drying chamber of the spray dryer device (spray dryer) using a nozzle. The organic solvent and water in the atomized droplets are volatilized in a very short time to prepare finely divided microcapsules. Examples of the nozzle include a two-liquid nozzle type, a pressure nozzle type, and a rotating disk type.
The microcapsules thus obtained are washed several times with distilled water as desired to remove free physiologically active substances, drug-retaining substances, emulsifiers and the like adhering to the surface of the microcapsules. Next, the washed microcapsules may be dried under reduced pressure, or redispersed in distilled water and then lyophilized to further remove the organic solvent.
[0035]
In addition, the physiologically active substance is 1) one kind of hydrophobic organic solvent (eg, dichloromethane, chloroform, dichloroethane, carbon tetrachloride, ethyl acetate, cyclohexane, etc.) and at least one kind of hydrophilic organic solvent (eg, methanol, ethanol, acetonitrile). 2) when dissolved in an oil phase consisting of a solution of a polymer and a hydrophobic organic solvent, or 3) at least one surfactant (eg, glycerin fatty acid) in the hydrophobic organic solvent. Ester, propylene glycol fatty acid ester, sucrose fatty acid ester, etc.) are dissolved in the oil phase, these oil phases are dispersed in the outer water phase used in the underwater drying method, and the O / W emulsion is dispersed. After the formation, the organic solvent in the oil phase is removed and the microcapsules are prepared in the same manner as in the case of the underwater drying method. And it can also be. Furthermore, microcapsules can be prepared by subjecting the O / W emulsion to the above-described phase separation method or spray drying method.
[0036]
The sustained-release preparation of the present invention preferably contains an excipient. The excipient is less toxic even when administered in vivo, is easy to dry such as freeze-drying or spray-drying, dissolves quickly when administered in vivo, or dissolves at the time of use. It is desirable to be. Examples of such excipients include sugars, cellulose derivatives, amino acids, proteins, polyacrylic acid derivatives, organic salts, and inorganic salts. These excipients may be used by mixing two or more kinds at an appropriate ratio.
Examples of the sugar include D-mannitol, sodium alginate, fructose, dextran, dextrin, sucrose, D-sorbitol, lactose, glucose, maltose, starches, and trehalose.
Examples of the cellulose derivative include carboxymethylcellulose, hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, and the like.
Examples of amino acids include glycine, alanine, tyrosine, arginine, lysine and the like.
Examples of the protein include gelatin, fibrin, collagen, albumin and the like.
Examples of the polyacrylic acid derivative include sodium polyacrylate, methacrylic acid / acrylic acid copolymer (Eudragit, manufactured by Rohm, Germany), and the like.
Examples of the organic salt include sodium citrate, sodium tartrate, sodium carbonate, potassium carbonate and the like.
Examples of the inorganic salt include sodium chloride, potassium chloride, sodium phosphate, potassium phosphate and the like.
As the excipient, in addition to the above, a water-soluble polymer that does not dissolve the polymer that is a base for sustained release preparation, such as polyvinyl pyrrolidone, polyvinyl alcohol, and the like is also used.
The excipient is preferably a saccharide, particularly D-mannitol, which is easy to freeze-dry and has low toxicity.
[0037]
The amount of excipient used is determined by the solubility of the excipient, the tonicity of the solution obtained by dissolving the excipient, viscosity, dispersibility, stability, etc., but when the sustained-release preparation is dried In addition, the content of the excipient in the dry sustained-release preparation is, for example, about 0.5 to about 99% (w / w), preferably about 1 to about 90% (w / w), more preferably about 2 to about Used to be 60% (w / w). When D-mannitol is used as an excipient, it is particularly preferable that the content of the excipient in the dry sustained-release preparation is about 2 to about 40% (w / w).
By the addition of these excipients, 1) the frequency of contact and impact of particles during and after drying of sustained release formulations (especially microspheres) is reduced, and the uniformity of particles during freeze drying or spray drying is reduced. 2) Drying at a temperature above the glass transition point of the sustained-release preparation is possible, and more complete removal of water or organic solvent is possible. 3) Stability of the sustained-release preparation over time It is improved, dispersibility is good, and it is not limited to cold storage, and excellent effects such as obtaining a sustained-release preparation having a long-term expiration date at room temperature can be obtained.
[0038]
In the present invention, a sustained-release preparation containing an excipient can be produced, for example, by mixing the microcapsules obtained by the above-mentioned drying method in water, phase separation method or spray drying method with an excipient. it can. The microcapsules may be those dried under reduced pressure after washing, or those redispersed in distilled water after washing and lyophilized. The mixing method is not particularly limited, and is performed using, for example, a mixer, but a method capable of obtaining a uniform mixture is preferable.
In addition, sustained-release preparations containing excipients can also be produced by spraying an aqueous solution of excipients from a separate nozzle simultaneously with the spraying of the W / O emulsion when, for example, microcapsules are produced by spray drying. can do.
Furthermore, sustained-release preparations containing excipients can be obtained by using an aqueous solution of excipients in the outer aqueous phase when producing W / O / W emulsions used in water drying and spray drying methods. Can also be manufactured.
The sustained-release preparation containing an excipient is preferably obtained by washing microcapsules obtained by an underwater drying method, a phase separation method or a spray drying method, and dissolving or suspending the washed microcapsules. It is produced by dispersing in distilled water and then freeze-drying or drying under reduced pressure. Alternatively, the washed microcapsules may be dispersed in distilled water, and the excipient may be dissolved or suspended in the resulting dispersion, followed by lyophilization or vacuum drying. In particular, the washed microcapsules are dispersed in distilled water in which the excipient is dissolved, or the excipient is dissolved in a dispersion obtained by dispersing the washed microcapsules in distilled water and then freeze-dried. Thus, a uniform mixture can be obtained.
[0039]
Furthermore, if desired, the microcapsules obtained by the above-mentioned underwater drying method, phase separation method, or spray drying method may be adhered to each other at a temperature above the glass transition temperature (Tg) of the polymer used as the base. By heating to a temperature that does not, the water and organic solvent in the microcapsules can be removed more completely and the sustained release can be improved. At this time, the organic solvent is preferably removed to less than about 1000 ppm, preferably less than about 500 ppm, more preferably less than about 100 ppm.
The glass transition temperature refers to a midpoint glass transition temperature obtained when a differential scanning calorimeter (DSC) is used and the heating rate is increased at 10 or 20 ° C. per minute.
The timing of heating is preferably after the excipient is added if desired, and then the microcapsules are freeze-dried or dried under reduced pressure, but are not particularly limited, and may be, for example, after subdivision.
[0040]
If the heating temperature is lower than the glass transition temperature of the polymer used as a base, removal of water or organic solvent may not be sufficient, and if the temperature is too high, microcapsule fusion, deformation, degradation of bioactive substances, degradation, etc. Because the danger increases, the heating temperature cannot be generally defined, but the physical properties of the polymer used as the base (eg, molecular weight, stability, etc.), physiologically active substance, average particle diameter of microcapsules, heating time, microcapsules It can be determined appropriately in consideration of the degree of drying, the heating method, etc.
The heating temperature is preferably from the glass transition temperature of the polymer used as the base to a temperature not higher than about 30 ° C higher than the glass transition temperature, more preferably from the glass transition temperature of the polymer to not higher than about 20 ° C higher than the glass transition temperature. Temperature.
[0041]
Although the heating time varies depending on the heating temperature, the amount of microcapsules to be treated, etc., generally, the temperature of the microcapsules themselves reaches a predetermined temperature for about 6 to about 120 hours, more preferably about 12 to about 96. It's time. In addition, the upper limit of the heating time is not particularly limited as long as the residual organic solvent and moisture are less than the allowable values, but the microcapsules soften under the condition of the glass transition temperature or higher, and the microcapsules are in physical contact with each other or the microcapsules are laminated. Since it is deformed by the load of time, it is preferable to quickly finish the heating when the remaining organic solvent and moisture are below allowable values.
The heating method is not particularly limited, and any method may be used as long as the microcapsules are uniformly heated. Preferable specific examples of the heating method include, for example, a method of heating and drying under reduced pressure using a freeze dryer, a reduced pressure thermostat or the like.
[0042]
The sustained-release preparation of the present invention includes, for example, injections, implants, oral preparations (eg, powders, granules, capsules, tablets, syrups, emulsions, suspensions, etc.), nasal preparations, suppositories (For example, rectal suppositories, vaginal suppositories, etc.) may be used. These preparations can be produced by known methods generally used in the field of preparations.
For example, an injection is produced by dispersing the above-described microcapsules in an aqueous or oily dispersion medium. Examples of the aqueous dispersion medium include isotonic agents (eg, sodium chloride, glucose, D-mannitol, sorbitol, glycerin, etc.) and dispersants (eg, Tween 80, HCO-50, HCO-60, carboxymethylcellulose) in distilled water. , Sodium alginate, etc.), preservatives (eg, benzyl alcohol, benzalkonium chloride, phenol, etc.), soothing agents (eg, glucose, calcium gluconate, procaine hydrochloride, etc.) and the like. Examples of the oil dispersion medium include olive oil, sesame oil, peanut oil, soybean oil, corn oil, and medium chain fatty acid glycerides.
The injection may be filled in the chamber of the prefilled syringe, or the dispersion medium and the microcapsule may be separated and filled in different chambers in a so-called double chamber prefilled syringe (DPS).
In addition, when manufacturing an injection, in addition to the above composition, an excipient (eg, mannitol, sorbitol, lactose, glucose, etc.) is further added to the microcapsule and redispersed, followed by freeze drying or spray drying. Then, solidified, and when used, distilled water for injection or a suitable dispersion medium is added to obtain a more stable sustained-release injection.
[0043]
Preparations for oral administration include, for example, the above-described microcapsules, excipients (eg, lactose, sucrose, starch, etc.), disintegrants (eg, starch, calcium carbonate, etc.), binders (eg, starch, gum arabic, carboxymethylcellulose). , Polyvinyl pyrrolidone, hydroxypropyl cellulose, etc.), lubricant (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.), etc. are added and compression molded, and then masking of taste, enteric properties or sustainability as required For this purpose, it can be produced by coating by a method known per se. Examples of the coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Brulon F68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (manufactured by ROHM) , Germany, methacrylic acid / acrylic acid copolymer) and dyes (eg, titanium oxide, bengara, etc.).
[0044]
The nasal preparation may be solid, semi-solid, or liquid. The solid nasal preparation may be, for example, the above-mentioned microcapsules as they are, but usually the microcapsules are filled with excipients (eg, glucose, mannitol, starch, microcrystalline cellulose, etc.), thickeners (eg, , Natural gums, cellulose derivatives, acrylic acid polymers, etc.) and the like. For example, a liquid nasal preparation can be produced in the same manner as in the case of the injection described above. In addition, these nasal preparations all have pH adjusters (eg, carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc.), preservatives (eg, p-hydroxybenzoates, chlorobutanol, chloride) Benzalkonium etc.) may be included.
[0045]
The suppository may be oily or aqueous, and may be solid, semi-solid or liquid. Suppositories are usually produced using an oily base, an aqueous base or an aqueous gel base. Examples of the oil base include glycerides of higher fatty acids (eg, cacao butter, witepsols (Dynamite Nobel, Germany), etc.), intermediate fatty acids (eg, miglyols (Dynamite Nobel, Germany)), or vegetable oils (eg, , Sesame oil, soybean oil, cottonseed oil, etc.). Examples of the aqueous base include polyethylene glycols and propylene glycol. Examples of the aqueous gel base include natural gums, cellulose derivatives, vinyl polymers, and acrylic acid polymers.
[0046]
The sustained-release preparation of the present invention is preferably an injection. When the sustained-release preparation of the present invention is an injection, the particle size of microparticles such as microcapsules in the injection may be in a range that satisfies the dispersibility and needle penetration. For example, the average diameter is about 1 To about 300 μm, preferably about 5 to about 100 μm.
[0047]
The sustained-release preparation of the present invention has low toxicity and can be safely administered to mammals (eg, mouse, rat, dog, cat, sheep, pig, horse, cow, monkey, human etc.).
The dosage of the sustained-release preparation of the present invention varies depending on the type and content of the physiologically active substance, the sustained-release period of the physiologically active substance, the subject of administration, the purpose of administration, etc., but may be any effective amount of the physiologically active substance.
When the sustained-release preparation of the present invention is used for humans, the dose is, for example, about 1 mg to about 10 g, preferably about 10 mg to about 2 g per adult (body weight 50 kg). It can be suitably selected from the range. When the sustained-release preparation is an injection, the volume of the suspension can be appropriately selected from the range of about 0.1 to about 5 ml, preferably about 0.5 to about 3 ml.
In particular, when the physiologically active substance is leuprorelin or leuprorelin acetate, the sustained-release preparation of the present invention can be used for hormone-dependent diseases (eg, prostate cancer, prostatic hypertrophy, breast cancer, endometriosis, uterus). It is effective for myoma, central precocious puberty, etc.) and contraception. The dose of the sustained release preparation per adult (body weight 50 kg) per month is, for example, about 1.88 to about 7.5 mg as a physiologically active substance. For example, for a 6 month sustained release formulation, the single dose of leuprorelin or leuprorelin acetate is about 11.3 to about 45 mg, and the single dose of the sustained release formulation is about 75 to about 800 mg. is there.
On the other hand, when the sustained-release preparation of the present invention is administered to livestock (eg, dogs, cats, sheep, pigs, horses, cows, monkeys, etc.) for the purpose of contraception or meat softening, the dosage is It is set by measuring the clearance of the animal to be administered. For example, when the animal to be administered is a dog, the dose per month of the sustained release preparation is, for example, about 0.03 to about 1.5 mg / kg as a physiologically active substance. For example, in a sustained-release preparation for 6 months, a single dose of the physiologically active substance is about 0.18 to about 9 mg / kg, and a single dose of the sustained-release preparation is about 1.2 to about 200 mg / kg. is there.
[0048]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the present invention will be described more specifically with reference to reference examples, examples, comparative examples, and experimental examples. However, the present invention is not limited to these examples as long as the gist thereof is not exceeded.
Further, the following% (percent) indicates weight percent unless otherwise specified.
[0049]
【Example】
Reference example 1
DL-polylactic acid having a weight average molecular weight of 79,900 (RESORMER, R206, Lot No. 211967, manufactured by Boehringer Ingelheim, Germany) (hereinafter abbreviated as polymer F) synthesized by a ring-opening polymerization method was added to 10 g of DL- The lactic acid was hydrolyzed by dipping in 400 ml of a solution (pH 2.09, pH 2.27, respectively) diluted 1/50 or 1/100 (w / w) times with distilled water at 60 ° C.
Subsequently, the hydrolyzed polylactic acid was taken out from the obtained mixed solution, dissolved in 500 ml of dichloromethane, respectively, and then washed three times with 1,000 ml of distilled water for 30 minutes each to remove water-soluble oligomers. The organic solvent phase was taken in a glass petri dish, dichloromethane was evaporated and dried at 40 ° C. under reduced pressure for 1 day. Before the organic solvent phase was completely solidified, the degree of vacuum was adjusted to foam the lactic acid polymer, and the volume of the lactic acid polymer was increased to promote the evaporation of dichloromethane. The obtained foam was pulverized to obtain polymers shown in Table 1.
[Table 1]
[0050]
Reference example 2
In the same manner as in Reference Example 1, polymer F was hydrolyzed to obtain the polymers shown in Table 2.
[Table 2]
[0051]
Example 1
Using the various polymers produced in Reference Example 1, microspheres shown in Table 3 were produced by an underwater drying method.
Namely, 550 mg of leuprorelin acetate is dissolved in 1 ml of distilled water. A solution obtained by dissolving 4 g of the polymer produced in Reference Example 1 in dichloromethane was added to the resulting solution, and the mixture was stirred and emulsified with a small homogenizer (Polytron, manufactured by Kinematica, Switzerland) for about 1 minute to obtain a W / O emulsion. The W / O emulsion is cooled to 13 ° C and then added to 1,000 ml of a 0.25% polyvinyl alcohol (PVA) aqueous solution previously cooled to the same temperature, and a homomixer (specialized machine, Japan) (rotation speed: about 7,000 rpm) Was used to obtain a W / O / W emulsion. The W / O / W emulsion was desolvated for about 3 hours while stirring gently. The resulting microspheres were separated by centrifugation after removing coarse particles through a 74 μm sieve. The resulting residue was washed three times with distilled water to remove free drug and PVA, and then redispersed with a small amount of water and freeze-dried.
[Table 3]
[0052]
Comparative Example 1
Polymers D and E prepared in Reference Example 2, DL-polylactic acid having a weight average molecular weight of 22,200 (RESOMER, R203, Lot No. 15004, manufactured by Boehringer Ingelheim, Germany) (hereinafter abbreviated as polymer G), weight average molecular weight 47,200 DL-polylactic acid (PL-50000, manufactured by Taki Chemical Co., Ltd., Japan) (hereinafter abbreviated as polymer H) and polymer obtained by washing polymer H with water (hereinafter abbreviated as polymer H ′) were used. In the same manner as in Example 1, microspheres shown in Table 4 were produced.
[Table 4]
[0053]
Example 2
Dissolve 6 g of leuprorelin acetate in 10 ml of distilled water. To the resulting solution was added 44 g of the polymer B produced in Reference Example 1 in dichloromethane and then filtered, and 190 g of the resulting solution was stirred and emulsified with an auto minimixer (rotation speed: 6,000 rpm) for 8 minutes. Get an / O emulsion. The W / O emulsion is cooled to about 13 ° C. and then added to 12 L of a 0.1% PVA aqueous solution that has been cooled to the same temperature in advance. A homomic line flow (specialized machine, Japan) (rotation speed: about 7,000 rpm) And emulsify to obtain a W / O / W emulsion. The W / O / W emulsion is desolvated for about 3 hours while stirring gently. The obtained microspheres are separated and washed in the same manner as in Example 1, and then redispersed with a small amount of water. In the resulting dispersion, 6.4 g of D-mannitol is dissolved, sieved and lyophilized. The shelf temperature at the time of drying is gradually increased, and it is dried at 53 ° C. for 48 hours. The resulting dried product is sieved to obtain a microsphere powder. This operation yields about 48 g of microsphere powder containing about 15% mannitol.
[0054]
Example 3
Peptide A1 acetate 4 g is dissolved in 6 ml distilled water. To the resulting solution was added 110 g of a solution obtained by dissolving 30 g of the polymer B produced in Reference Example 1 in dichloromethane and then filtering, and the mixture was stirred and emulsified with an auto minimixer (rotation number: 6,000 rpm) for 5 minutes. Get an / O emulsion. The W / O emulsion is cooled to about 13 ° C. and then added to 7 L of a 0.1% PVA aqueous solution that has been cooled to the same temperature in advance. Subsequently, a microsphere powder is obtained in the same manner as in Example 2 except that the amount of D-mannitol is 4.3 g. By this operation, about 33 g of microsphere powder containing about 15% mannitol is obtained.
[0055]
Example 4
Dissolve 7.5 g somatostatin in 13 ml distilled water. To the obtained solution, 100 g of polymer A produced in Reference Example 1 was dissolved in 250 ml of dichloromethane and then filtered, and the resulting solution was stirred and emulsified with an auto minimixer (rotation speed: 6,000 rpm) for 5 minutes. Get an / O emulsion. The W / O emulsion is cooled to about 14 ° C. and then added to 25 L of a 0.1% PVA aqueous solution that has been cooled to the same temperature in advance. Next, a microsphere powder is obtained in the same manner as in Example 2 except that the amount of D-mannitol is 13.7 g and the drying conditions are 54 ° C. for 24 hours. By this operation, about 100 g of microsphere powder containing about 15% mannitol is obtained.
[0056]
Example 5
Dissolve 2 g of h-GH (human growth hormone) and 2 g of arginine in 5 ml of distilled water. To the obtained solution, 30 g of polymer B produced in Reference Example 1 was dissolved in 96 g of dichloromethane and then filtered, and the resulting solution was stirred and emulsified with an auto minimixer (rotation speed: 6,000 rpm) for 5 minutes. Get an / O emulsion. The W / O emulsion is cooled to about 13 ° C. and then added to 3 L of a 0.1% PVA aqueous solution that has been cooled to the same temperature in advance. Subsequently, a microsphere powder is obtained in the same manner as in Example 2 except that the amount of D-mannitol is 4 g and the drying conditions are 52 ° C. and 24 hours. By this operation, about 30 g of microsphere powder containing about 15% mannitol is obtained.
[0057]
Example 6
The microspheres (2.97 mg as the drug) produced in Example 1 were dispersed in 0.5 ml of a dispersion medium (an aqueous solution containing 1% sodium carboxymethyl cellulose and 0.5% Tween 80) to produce an injection.
[0058]
Comparative Example 2
Microspheres (2.97 mg as a drug) produced in Comparative Example 1 were dispersed in 0.5 ml of a dispersion medium (an aqueous solution containing 1% sodium carboxymethyl cellulose and 0.5% Tween 80) to produce an injection.
[0059]
Experimental example 1
The water-soluble oligomer (free acid) content of the polymer produced in Reference Example 1 and commercially available polylactic acid (polylactic acid produced by a ring-opening polymerization method and not hydrolyzed) was measured. As commercially available polylactic acid, polymer F used in Reference Example 1 and polymers G and H used in Comparative Example 1 were used.
To measure the free acid content, weigh approximately 150 mg of each polymer, dissolve in 5 ml of dichloromethane, extract with shaking with 10 ml of distilled water for 10 minutes, and centrifuge at 3,000 rpm for 8 minutes. 2.5 ml of the phase was taken and titrated with 1 mM aqueous sodium hydroxide using phenol red as a titrant. The results are shown in Table 5.
It should be noted that the free acid content of the polymer is an important factor affecting the initial release of the drug and the polymer stability, and the initial burst through the aqueous channel due to the free acid, ie the “tunnel effect”, is 0.1% free acid. % Is known to be prominent (Pharmaceutical Research, 11, (8) 1143-1147 (1994)).
[0060]
[Table 5]
As is clear from Table 5, the free acid content of the polymer obtained in Reference Example 1 was lower than the free acid content of commercially available polylactic acid.
[0061]
Experimental example 2
The glass transition temperatures (Tg) of polymers A to H and H 'were measured. The results are shown in Table 6.
[Table 6]
[0062]
Experimental example 3
The glass transition temperature (Tg), drug content, and trap rate of the microspheres produced in Example 1 and Comparative Example 1 were measured. The results are shown in Table 7.
[Table 7]
[0063]
As is clear from Table 7, the microspheres produced using the polymer (polymers G and H) not hydrolyzing polylactic acid produced by ring-opening polymerization and the polymer (polymer H ′) obtained by washing the polymer H with water (polymer H ′) In the microspheres G, H and H ′), the drug content and the trap rate were low. Further, as apparent from Tables 3 and 4, the yield of these microspheres was low.
Furthermore, even if the polymer is obtained by hydrolyzing polylactic acid produced by ring-opening polymerization, microspheres (microspheres D and E) produced using polymers (polymers D and E) having a molecular weight greater than 60,000 are not suitable. The trap rate was slightly low. Further, as apparent from Tables 3 and 4, the yield of these microspheres was low.
There are many cyclic polymers in the polymer that is not subjected to hydrolysis treatment, and there are few polylactic acids having a carboxylic acid group at the terminal. Therefore, in the microspheres produced using such a polymer, the interaction between the polymer and the drug is small, and the trapping effect of the drug particles by the polymer is small, so that the trap rate is considered to decrease.
Further, when the molecular weight of the polymer is increased, the ratio of the hydrophilic carboxylic acid group to the hydrophobic group of the polymer is decreased. Therefore, even in the microspheres produced using such a polymer, it is considered that the effect of encapsulating drug particles by the polymer is reduced and the trap rate is lowered.
Therefore, in order to successfully incorporate the drug in the microsphere, it is considered that the presence of a carboxylic acid group having an appropriate ratio to the hydrophobic alkyl group is required at the end of the polymer chain.
[0064]
Experimental Example 4
The injection produced in Example 6 and Comparative Example 2 was subcutaneously administered to rats [dose: 2.97 mg / rat (30 μg / kg / day) as drug, n = 5], and then the drug remained subcutaneously over time (Luprorelin acetate) was quantified to evaluate drug release. The results are shown in Table 8.
[Table 8]
As is evident from Table 8, the microspheres of the present invention (microspheres A and B) had a low initial burst and then almost continuously zero-order release of drug over a long period of about 6 months. On the other hand, despite the use of polylactic acid with a large molecular weight and slow biodegradability, microspheres D and E not only have a large initial burst, but also release most of the drug at 17 weeks, followed by subsequent release. Was hardly seen.
[0065]
【The invention's effect】
By using the polymer of the present invention, a sustained-release preparation (especially microsphere) having a high yield, a high drug uptake rate and a high drug content, and a small initial burst can be produced. Furthermore, since the polymer of the present invention does not substantially contain harmful catalysts, organic solvents and the like, it is highly safe.
The sustained-release preparation of the present invention has good dispersibility and excellent operability. The sustained-release preparation is excellent in storage stability and can be stored for a long time. Furthermore, the sustained-release preparation of the present invention can release the physiologically active substance almost continuously to the zero order over a long period of about 5 months or longer.
Claims (16)
(Pyr)Glu-R1-Trp-Ser-R2-R3-R4-Arg-Pro-R5 (I)
[式中、R1はHis,Tyr,Trpまたはp-NH2-Phe;R2はTyrまたはPhe;R3はGlyまたはtert-ブチル、tert-ブトキシ、tert-ブトキシカルボニル、メチル、ジメチル、トリメチル、2-ナフチル、インドリル-3-イル、2-メチルインドリルおよびベンジル-イミダゾ-2-イルから選択される置換基を有していてもよい、D-Leu,Ile,Nle,Val,Nval,Abu,Phe,Phg,Ser,Thr,Met,Ala,Trp,およびα-Aibuから選択されるD型のアミノ酸残基;R4はLeu,IleまたはNle;R5はGly-NH-R6(R6は水素原子または水酸基を有しまたは有しないC 1−4 アルキル基)またはNH-R7(R7は水素原子、アミノまたは水酸基を有しまたは有しないC 1−4 アルキル基、またはウレイド)を示す]で表されるペプチドまたはその塩である請求項8記載の徐放性製剤。LHRH agonist is formula
(Pyr) Glu-R 1 -Trp-Ser-R 2 -R 3 -R 4 -Arg-Pro-R 5 (I)
[Wherein R 1 is His, Tyr, Trp or p-NH 2 -Phe; R 2 is Tyr or Phe; R 3 is Gly or tert-butyl, tert-butoxy, tert-butoxycarbonyl, methyl, dimethyl, trimethyl Optionally having a substituent selected from 2-naphthyl, indolyl-3-yl, 2-methylindolyl and benzyl-imidazol-2-yl , D-Leu, Ile, Nle, Val, Nval, D-type amino acid residues selected from Abu, Phe, Phg, Ser, Thr, Met, Ala, Trp, and α-Aibu ; R 4 is Leu, Ile or Nle; R 5 is Gly-NH-R 6 ( R 6 is a C 1-4 alkyl group with or without a hydrogen atom or hydroxyl group) or NH—R 7 (R 7 is a C 1-4 alkyl group with or without a hydrogen atom, amino or hydroxyl group, or ureido. The sustained-release preparation according to claim 8, which is a peptide represented by the formula:
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-
1997
- 1997-10-30 PT PT97308692T patent/PT839525E/en unknown
- 1997-10-30 EP EP97308692A patent/EP0839525B1/en not_active Expired - Lifetime
- 1997-10-30 DE DE69730093T patent/DE69730093T2/en not_active Expired - Lifetime
- 1997-10-30 DK DK97308692T patent/DK0839525T3/en active
- 1997-10-30 CA CA002219698A patent/CA2219698C/en not_active Expired - Fee Related
- 1997-10-30 AT AT97308692T patent/ATE272394T1/en not_active IP Right Cessation
- 1997-10-30 ES ES97308692T patent/ES2221019T3/en not_active Expired - Lifetime
- 1997-10-31 US US08/962,347 patent/US6113943A/en not_active Expired - Lifetime
- 1997-10-31 JP JP29977897A patent/JP4361144B2/en not_active Expired - Lifetime
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2000
- 2000-03-07 US US09/520,150 patent/US6699500B2/en not_active Expired - Lifetime
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EP0839525B1 (en) | 2004-08-04 |
ES2221019T3 (en) | 2004-12-16 |
US20020031545A1 (en) | 2002-03-14 |
CA2219698C (en) | 2007-09-04 |
US6699500B2 (en) | 2004-03-02 |
PT839525E (en) | 2004-10-29 |
JPH10182496A (en) | 1998-07-07 |
CA2219698A1 (en) | 1998-04-30 |
US6113943A (en) | 2000-09-05 |
ATE272394T1 (en) | 2004-08-15 |
EP0839525A1 (en) | 1998-05-06 |
DE69730093T2 (en) | 2006-07-20 |
DE69730093D1 (en) | 2004-09-09 |
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